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Hirschsprung Disease 
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Hirschsprung disease is a congenital anomaly of innervation of the lower intestine, usually limited to the colon, resulting in partial or total functional obstruction. Symptoms are obstipation and distention. Diagnosis is by barium enema and rectal biopsy. Anal manometry can help in the evaluation and reveals lack of relaxation of the internal anal sphincter. Treatment is surgical.

Hirschsprung disease is caused by congenital absence of the Meissner and Auerbach autonomic plexus in the intestinal wall. The estimated incidence is 1 in 5000 live births. Disease is usually limited to the distal colon (75% of cases) but can involve the entire colon or even the entire large and small bowels; the denervated area is always contiguous. Males are more commonly affected (male:female ratio 4:1) unless the entire colon is involved, in which case there is no gender difference.

Peristalsis in the involved segment is absent or abnormal, resulting in continuous smooth muscle spasm and partial or complete obstruction with accumulation of intestinal contents and massive dilation of the more proximal, normally innervated intestine.

Symptoms and Signs
Patients most commonly present early in life, but some do not present until childhood or even adulthood.

Normally, 98% of neonates pass meconium in the first 24 h of life. About 40% of neonates with Hirschsprung disease fail to pass meconium in the first 24 h of life. Infants present with obstipation, abdominal distention, and, finally, vomiting as in other forms of distal bowel obstruction. Occasionally, infants with ultra-short segment aganglionosis have only mild or intermittent constipation, often with intervening bouts of mild diarrhea, resulting in delay in diagnosis. In older infants, symptoms and signs may include anorexia, lack of a physiologic urge to defecate, and, on digital rectal examination, an empty rectum with stool palpable higher up in the colon and an explosive passage of stool upon withdrawal of the examining finger (blast sign). Infants may also fail to thrive.

Diagnosis
• Barium enema
• Rectal biopsy
• Sometimes rectal manometry
Diagnosis should be made as soon as possible. The longer the disease goes untreated, the greater the chance of developing Hirschsprung enterocolitis (toxic megacolon), which may be fulminant and fatal. Most patients can be diagnosed in early infancy.

Initial approach is typically with barium enema or sometimes rectal suction biopsy. Barium enema may show a transition in diameter between the dilated, normally innervated colon proximal to the narrowed distal segment (which lacks normal innervation). Barium enema should be done without prior preparation, which can dilate the abnormal segment, rendering the test nondiagnostic. Because characteristic findings may not be present in the neonatal period, a 24-h postevacuation x-ray should be taken; if the colon is still filled with barium, Hirschsprung disease is likely. A rectal suction biopsy can disclose the absence of ganglion cells. Acetylcholinesterase staining can be done to highlight the enlarged nerve trunks. Some centers also can do rectal manometrics, which can reveal lack of relaxation of the internal anal sphincter that is characteristic of the abnormal innervation. Definitive diagnosis requires a full-thickness biopsy of the rectum or colon to identify the full extent of the disease and thus plan surgical treatment.

Treatment
• Surgical repair
Treatment in the neonate typically involved a colostomy proximal to the aganglionic segment to decompress the colon and allow the neonate to grow before the 2nd stage of the procedure. Later resection of the entire aganglionic portion of the colon and a pull-through procedure is done. However, a number of centers now do a 1-stage procedure in the neonatal period. Results using laparoscopic technique are similar to those of the open method and are associated with shorter hospitalizations, earlier initiation of feeding, and less pain.

After definitive repair, the prognosis is good, although a number of infants have chronic dysmotility with constipation, obstructive problems, or both.

Key Points
• Congenital denervation affects the distal colon and less often larger regions of the colon and sometimes even the small bowel.
• Infants typically present with findings of distal bowel obstruction, such as obstipation, abdominal distention, and vomiting.
• Barium enema findings (done without prior preparation) and rectal manometry are highly suggestive; diagnosis is confirmed by rectal biopsy.
• The affected segment is resected surgically.

CLINICAL VIGNETTES

A 12-month-old infant presents with bilious vomiting and abdominal distention for 10 hours. His mother states that the infant has been constipated since birth and failed to pass meconium during the first 48 hours of life. On examination, he is very irritable. His length and weight are both below the 5th percentile according to his age. His abdomen is moderately distended. After a digital rectal examination, a fair amount of stool ejects out from the anus. Which of the following is the most likely diagnosis? 

A. Duodenal atresia
B. Intussusception
C. Hirschsprung disease
D. Malrotation
E. Pyloric stenosis

C. This infant has Hirschsprung disease, or congenital aganglionic bowel disease. It is five times more common in boys than in girls. It results from congenital absence of ganglion cells in either part of or the entire wall of the colon, resulting in a state of chronic contraction. In most cases, the aganglionic segment is limited to the rectosigmoid colon. In very rare cases, part of or the entire small bowel can be aganglionic as well. Bilious or feculent vomiting, abdominal distention, and constipation are the classic clinical signs. There might also be a history of failure to pass meconium in the first 48 hours of life. If only a short segment of the colon is involved, Hirschsprung disease might not be evident until in childhood or adolescence. Megacolon proximal to the aganglionic segment might be visible on barium enema. The diagnosis is confirmed with the demonstration of an aganglionic segment of the bowel on punch biopsy. 

Duodenal atresia (choice A) usually presents with vomiting. A "double bubble" sign is seen on abdominal radiography. Thirty to forty percent of cases are associated with Down syndrome. Intussusception (choice B) is certainly in the differential diagnosis of vomiting and abdominal distention. In this case, however, the history of failure to pass meconium in the newborn period and failure to thrive is much more suggestive of Hirschsprung disease. Intussusception occurs when one segment of the bowel telescopes into another segment just distal to it. The most common site of intussusception is the ileocolic junction. Malrotation (choice D) is usually caused by the presence of a volvulus, which presents with sudden onset of bilious vomiting, abdominal distention, rectal hemorrhage, peritonitis, and shock. It is a surgical emergency. Pyloric stenosis (choice E) usually presents with projectile vomiting in the first 2 or 3 weeks of life. On examination, an olive-shaped mass is usually palpable in the epigastric area. It is caused by hypertrophy and hyperplasia of the antrum of the stomach, resulting in obstruction. It occurs in 1 of 150 boys and in 1 of 750 girls. 

A normal birthweight, term baby with high APGAR scores fails to pass meconium within 36 hours of birth. The neonate also has a distended abdomen and has been vomiting and feeding poorly. Digital rectal examination temporarily relieves the obstruction, but the baby fails to pass stool thereafter. Barium enema examination demonstrates a very narrow distal segment of rectum with proximal dilation. Abnormalities of which of the following are most likely etiologically
related to this baby's disorder?

A. Chloride channels
B. Ganglion cells
C. Mucosal cells
D. Smooth muscle cells
E. Vagus nerve

The correct answer is B. The disease is Hirschsprung's disease, which is a congenital cause of constipation caused by an absence of ganglion cells in both the submucosal and intermyenteric plexus of a segment of bowel. The aganglionic bowel segment is narrowed because the lack of peristalsis keeps stool from moving into the segment. The distal rectum is always involved, and the lesion can extend proximally anywhere from a few centimeters past the rectum all the way up to the small intestine. The bowel proximal to the lesion is usually dilated. In this patient’s case, rectal examination dilated the narrowed aganglionic bowel, temporarily allowing passage of stool. Definitive treatment consists of surgical removal of the affected segment.

Failure to pass meconium is also characteristic of cystic fibrosis, a disorder of chloride channels (choice A). The characteristic radiologic appearance of the bowel in this case strongly suggests Hirschsprung's disease.

The mucosa (choice C) is not directly affected by Hirschsprung's disease, although a life- threatening (20% mortality) secondary enterocolitis may develop.

Smooth muscle (choice D) changes are not usually apparent on biopsy of aganglionic segments of bowel in Hirschsprung's disease.

Abnormalities of the vagus nerve (choice E) are not related to the aperistalsis in Hirschsprung's disease.
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DiGeorge Syndrome 
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DiGeorge syndrome is thymic and parathyroid hypoplasia or aplasia leading to T-cell immunodeficiency and hypoparathyroidism.

DiGeorge syndrome results from gene deletions in the DiGeorge chromosomal region at 22q11, mutations in genes at chromosome 10p13, and mutations in other unknown genes, which cause dysembryogenesis of structures that develop from pharyngeal pouches during the 8th wk of gestation. Most cases are sporadic; boys and girls are equally affected. DiGeorge syndrome may be partial (some T-cell function exists) or complete (T-cell function is absent).

Infants have low-set ears, midline facial clefts, a small receding mandible, hypertelorism, a shortened philtrum, developmental delay, and congenital heart disorders (eg, interrupted aortic arch, truncus arteriosus, tetralogy of Fallot, atrial or ventricular septal defects). They also have thymic and parathyroid hypoplasia or aplasia, causing T-cell deficiency and hypoparathyroidism. Recurrent infections begin soon after birth, but the degree of immunodeficiency varies considerably, and T-cell function may improve spontaneously. Hypocalcemic tetany appears within 24 to 48 h of birth.

Diagnosis
Immune function assessment with Ig levels, vaccine titers, and lymphocyte subset counts
Parathyroid function assessment
Chromosome analysis
Diagnosis is based on clinical findings. An absolute lymphocyte count is done, followed by B- and T-cell counts and lymphocyte subsets if leukopenia is detected; blood tests to evaluate T-cell and parathyroid function are done. Ig levels and vaccine titers are measured. If complete DiGeorge syndrome is suspected, the T-cell receptor excision circle (TREC) test should also be done.

A lateral chest x-ray may help evaluate thymic shadow.

Fluorescent in situ hybridization (FISH) testing can detect the chromosomal deletion in the 22q11 region; standard chromosomal tests to check for other abnormalities may also be done.

If DiGeorge syndrome is suspected, echocardiography is done. Cardiac catheterization may be necessary if patients present with cyanosis.

Treatment
• Partial syndrome: Ca and vitamin D supplementation
• Complete syndrome: Transplantation of cultured thymus tissue or hematopoietic stem cells
In partial DiGeorge syndrome, hypoparathyroidism is treated with Ca and vitamin D supplementation; long-term survival is not affected. Complete DiGeorge syndrome is fatal without treatment, which is transplantation of cultured thymus tissue or hematopoietic stem cell transplantation.

CLINICAL VIGNETTES

An alert pediatric intern notices that a neonate with dysmorphic facies is twitching abnormally. As he watches, the baby experiences a seizure. Stat laboratories indicate a glucose of 90, serum sodium of 140, serum potassium of 4.2 and serum calcium of 3.9. Over the next several months, the child is admitted to the hospital twice for Candida infections, and once for a viral exanthem. Which of the following is the most likely diagnosis? 

A. Ataxia telangiectasia
B. Bruton's hypogammaglobulinemia
C. DiGeorge syndrome
D. Severe combined immunodeficiency
E. Wiskott-Aldrich syndrome

The correct answer is C. DiGeorge syndrome is due to fetal malformation of epithelial elements of the third and fourth pharyngeal pouches, leading to thymic aplasia or severe hypoplasia and sometimes, absence of the parathyroids. Clinically, the condition is classified as a selective T-cell deficiency, but varying degrees of deficiency of antibody production may also be seen. Affected infants are susceptible to fungal and viral infections, and may exhibit tetany due to severe hypocalcemia.

In autosomal recessive ataxia telangiectasia (choice A), progressive cerebellar ataxia is accompanied by multiple telangiectasias on exposed skin and a variable, usually moderate, immunodeficiency that may involve both antibody production and cell-mediated immunity. Chronic or recurrent sinus and pulmonary infections result in bronchiectasis. 

In Bruton's (X-linked) agammaglobulinemia (choice B), children have normal numbers of circulating T cells with very few circulating B cells and only tiny amounts of circulating antibody. Affected individuals have recurrent bacterial infections beginning late in the first year of life.

Severe combined immunodeficiency (choice D) is actually a cluster of several diseases with variable genetics characterized by severely deficient T cell functions and variable (often depressed) antibody production. Multiple, sometimes simultaneous, infections with viruses, bacteria, and fungi occur.

Wiskott-Aldrich syndrome (choice E) is an X-linked disease with thrombocytopenia, lymphopenia, and decreased T cell function. Lymphoid malignancy (e.g., acute lymphocytic leukemia) may occur.

A 5-year-old boy suffers from a condition characterized by recurrent fungal and viral infections, thymic hypoplasia, tetany, and abnormal facies. Serum levels of immunoglobulins are mildly depressed, and lymph node biopsy shows lymphocyte depletion of T-dependent areas. Which of the following is the underlying pathogenetic mechanism? 

A. Developmental defect of the third/fourth pharyngeal pouches
B. In utero infection by human immunodeficiency virus (HIV)
C. Mutations of an autosomal gene encoding adenosine deaminase
D. Mutations of an X-linked gene coding for a cytokine receptor subunit
E. Mutations of an X-linked gene coding for a tyrosine kinase

A. The constellation of thymic hypoplasia, hypocalcemia (with tetany), abnormal facies, and congenital cardiac anomalies defines the condition known as DiGeorge syndrome. This results from a developmental failure of third and fourth pharyngeal pouches, which gives rise to congenital absence or anomalies of the parathyroid, thymus, lower face, and cardiac structures. Immune deficiency results from failure of T-lymphocytes to mature in the thymus. Thus, fungal and viral organisms, which are normally controlled by T-mediated mechanisms, become frequent causes of opportunistic infections. The underlying gene defect is related to 22q11 deletion, which results in two partially overlapping conditions, i.e. DiGeorge syndrome and velocardiofacial syndrome. 

These conditions are collectively referred to as chromosome 22q11 deletion syndrome. In utero infection by human immunodeficiency virus (HIV) (choice B) would result in T-cell deficiency but would not be associated with congenital abnormalities. Mutations of the autosomal gene encoding adenosine deaminase (choice C) represent the most common cause of the recessive form of severe combined immunodeficiency disease (SCID), encompassing a heterogeneous group of conditions characterized by deficiency of both T- and B-cell mechanisms. SCID may be autosomal dominant, autosomal recessive, or X-linked. Mutations of the X-linked gene coding for a cytokine receptor subunit (choice D) represent the most common cause of the autosomal dominant form of SCID. Mutation of an X-linked gene coding for a tyrosine kinase (choice E) is the underlying molecular mechanism leading to X-linked agammaglobulinemia of Bruton, a syndrome characterized by inability of pre-B cell precursors to mature into B-lymphocytes. Humoral immune deficiency thus manifests.

A 4-month-old male presents with twitching of the facial muscles. He has previously been seen for several severe episodes of Candida infections. On examination, the child has low-set ears, hypertelorism, and a shortened philtrum. What additional findings would be likely in this individual?

A. Absent thymic shadow on chest x-ray
B. Decreased alpha-fetoprotein 
C. Decreased IgA levels
D. Elevated IgM levels

The correct answer is A. The clinical findings describe DiGeorge syndrome. Patients clinically present with tetany (usually first noted in the facial muscles) due to hypocalcemia secondary to hypoparathyroidism. The thymus is absent, as are the parathyroid glands, due to failure of development of the 3rd and 4th pharyngeal pouches. Recurrent infections due to defective cellular immunity and abnormal facies are additional features.

Decreased alpha-fetoprotein (choice B) is an amniotic fluid marker for Down's syndrome. Down's syndrome patients have abnormal immune responses that predispose them to serious infections (particularly of the lungs) and to thyroid autoimmune disease. However, there is no defect of the parathyroid glands.

Decreased IgA levels (choice C) describes selective IgA deficiency, which is the most common hereditary immunodeficiency. The syndrome is due to a failure of heavy-chain gene switching in B cells.

Elevated IgM (choice D) is seen in hyper-IgM syndrome. Patients have a high concentration of IgM and normal numbers of T and B cells, but low levels of IgG, IgA, and IgE. Helper T cells have a defect in the surface protein CD40 ligand that interacts with CD40 on the B-cell surface. This results in an inability of the B cell to switch from the production of IgM to other classes of antibodies.
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Lesch-Nyhan 
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Lesch-Nyhan syndrome: This is a rare, X-linked, recessive disorder caused by deficiency of hypoxanthine-guanine phosphoribosyl transferase (HGPRT); degree of deficiency (and hence manifestations) vary with the specific mutation. HGPRT deficiency results in failure of the salvage pathway for hypoxanthine and guanine. These purines are instead degraded to uric acid. 

HGPRT is needed in the body to recycle purines, such as guanine back into its nucleotide, guanosine monophosphate (GMP). Without HGPRT excess guanine eventually breaks down into uric acid and accumulates in the brain.

Formation of DNA (during cell division) requires nucleotides, molecules that are the building blocks for DNA. The purine bases (adenine and guanine) and pyrimidine bases (thymidine and cytosine) are components of these nucleotides. Normally, the nucleotides are synthetized de novo from amino acids and other precursors. A small part, however, is 'recycled' from degraded DNA of broken-down cells. This is termed the "salvage pathway".

HGPRT is the "salvage enzyme" for the purines: it channels hypoxanthine and guanine back into DNA synthesis. Failure of this enzyme has two results:

Cell breakdown products cannot be reused, and are therefore degraded. This gives rise to increased uric acid, a purine breakdown product.

Hyperuricemia predisposes to gout and its complications. Patients also have a number of cognitive and behavioral dysfunctions, etiology of which is unclear; they do not seem related to uric acid. 

The disease usually manifests between 3 mo and 12 mo of age with the appearance of orange sandy precipitate (xanthine) in the urine; it progresses to CNS involvement with intellectual disability, spastic cerebral palsy, involuntary movements, and self-mutilating behavior (particularly biting, chewing off lips and fingertips if not restrained). Later, chronic hyperuricemia causes symptoms of gout (eg, urolithiasis, nephropathy, gouty arthritis, tophi). 

Diagnosis is suggested by the combination of dystonia, intellectual disability, and self-mutilation. Serum uric acid levels are usually elevated, but confirmation by HGPRT enzyme assay is usually done. 

CNS dysfunction has no known treatment; management is supportive. Self-mutilation may require physical restraint, dental extraction, and sometimes drug therapy; a variety of drugs has been used. Hyperuricemia is treated with a low-purine diet (eg, avoiding organ meats, beans, sardines) and allopurinol, a xanthine oxidase inhibitor (the last enzyme in the purine catabolic pathway). Allopurinol prevents conversion of accumulated hypoxanthine to uric acid; because hypoxanthine is highly soluble, it is excreted. 

CLINICAL VIGNETTES

A mentally retarded 10-year-old boy presents with arthritis, nephrolithiasis, and progressive renal failure. Since his first years of life, he manifested peculiar neurologic abnormalities consisting of self-mutilative biting of the lips and fingers, choreoathetosis, and spasticity. Two male relatives on his mother's side presented with a similar condition and died in their teens. Which of the following is the most likely diagnosis?

A. Chronic lead intoxication 
B. Fragile-X syndrome 
C. Gout 
D. Huntington disease 
E. Lesch-Nyhan syndrome 

E. Lesch-Nyhan syndrome was described in 1964 in two brothers who manifested self-mutilative behavior, choreoathetosis, and mental retardation beginning in their first year of life. This X-linked hereditary disorder is due to complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT), an enzyme that catalyzes the "salvage" pathway of purines. A salvage pathway deficiency results in increased "de novo" synthesis of purines, with consequent overproduction of uric acid. This is why patients with deficient HPRT develop hyperuricemia, with secondary uric acid stones, renal impairment, and gouty arthritis. Lesch-Nyhan syndrome is also characterized by self-mutilative behavior, choreoathetosis, and mental retardation, which manifestations are still largely unexplained. Renal failure is the most frequent cause of death.

Chronic lead intoxication (choice A) affects the nervous, gastrointestinal, and hematopoietic systems. Behavioral anomalies, hypochromic microcytic anemia, and peripheral neuropathies are the most common manifestations. Children are particularly vulnerable to lead intoxication. 

Fragile X syndrome (choice B) is the most common cause of mental retardation if Down syndrome is excluded. The condition is due to a triplet repeat expansion in the X chromosome and manifests with mental retardation and macroorchidism, among other, less common anomalies. 

Gout (choice C) is a systemic condition resulting from hyperuricemia. The joints and the organs are primarily affected, with recurrent attacks of acute arthritis most often involving the first metatarsophalangeal joint, ankle, heel, knee, wrist, fingers, and elbow. A positive family history is frequently present, but most cases are due to unknown metabolic defects resulting in overproduction or decreased excretion of uric acid. Extra-articular manifestations include formation of urate stones in the urinary tract, uric acid nephropathy, and tophi formation. 

Huntington disease (choice D) is an autosomal dominant neurodegenerative disorder caused by a triplet repeat expansion in a gene encoding a novel protein of unknown function. It manifests in the third or fourth decade with chorea and progressive dementia. Patients frequently present a strong propensity towards suicide. 

A baby that was apparently normal at birth begins to show a delay in motor development by 3 months of age. At one year of age, the child begins to develop spasticity and writhing movements. At age three, compulsive biting of fingers and lips and head-banging appear. At puberty, the child develops arthritis, and death from renal failure occurs at age 25. This patient's condition is due to an enzyme deficiency in which of the following biochemical pathways?

A. Ganglioside metabolism
B. Monosaccharide metabolism
C. Purine metabolism
D. Pyrimidine metabolism
E. Tyrosine metabolism

The correct answer is C. The patient has a classical case of Lesch-Nyhan syndrome, an X-linked disorder due to severe deficiency of the purine salvage enzyme hypoxanthine-guanine phosphoribosyl transferase (HPRT). This defect is associated with excessive de novo purine synthesis, hyperuricemia, and the clinical signs and symptoms described in the question stem. The biochemical basis of the often striking self-mutilatory behavior (which may require restraints and even tooth extraction) has never been established. Treatment with allopurinol inhibits xanthine oxidase and reduces gouty arthritis, urate stone formation, and urate nephropathy. It does not, however, modify the neurologic/psychiatric presentation.
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Henoch-Schonlein Purpura 
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Immunoglobulin A–associated vasculitis (IgAV—formerly called Henoch-Schönlein purpura-HSP) is vasculitis that affects primarily small vessels. It occurs most often in children. Common manifestations include palpable purpura, arthralgias, GI symptoms and signs, and glomerulonephritis. Diagnosis is clinical in children but usually warrants biopsy in adults. Disease is usually self-limited. Corticosteroids can relieve arthralgias and GI symptoms but do not alter the course of the disease. Progressive glomerulonephritis may require high-dose corticosteroids and cyclophosphamide.

IgA-containing immune complexes are deposited in small vessels of the skin and other sites, with consequent activation of complement. Possible inciting antigens include viruses that cause URIs, streptococcal infection, drugs, foods, insect bites, and immunizations. Focal, segmental proliferative glomerulonephritis is typical but mild.

Symptoms and Signs
The disease begins with a sudden palpable purpuric rash typically occurring on the feet, legs, and, occasionally, the trunk and arms. The purpura may start as small areas of urticaria that become palpable and sometimes hemorrhagic and confluent. Crops of new lesions may appear over days to several weeks. Many patients also have fever and polyarthralgia with periarticular tenderness and swelling of the ankles, knees, hips, wrists, and elbows.

GI symptoms are common and include colicky abdominal pain, abdominal tenderness, and melena. Intussusception occasionally develops in children. Stool may test positive for occult blood.

Symptoms usually remit after about 4 wk but often recur at least once after a disease-free interval of several weeks. In most patients, the disorder subsides without serious sequelae; however, some patients develop chronic renal failure.

Diagnosis
• Biopsy of skin lesions
IgAV is defined as vasculitis with IgA1-dominant immune deposits, affecting small vessels in the skin and GI tract and frequently causing arthritis. IgAV is also associated with glomerulonephritis indistinguishable from IgA nephropathy.

The diagnosis is suspected in patients, particularly children, with typical skin findings. It is confirmed by biopsy of skin lesions when leukocytoclastic vasculitis with IgA in the vessel walls is identified. Biopsy is unnecessary if clinical diagnosis is clear in children. Urinalysis is done; hematuria, proteinuria, and RBC casts indicate renal involvement.

CBC and renal function tests are done. If renal function is deteriorating, renal biopsy may help define the prognosis. Diffuse glomerular involvement or crescent formation in most glomeruli predicts progressive renal failure.

Treatment
Primarily corticosteroids and symptomatic measures
If the cause is a drug, it has to be stopped. Otherwise, treatment is primarily symptomatic. Corticosteroids (eg, prednisone 2 mg/kg up to a total of 50 mg po once/day) may help control abdominal pain and are occasionally needed to treat severe joint pain or renal disease. Pulse IV methylprednisolone followed by oral prednisone and cyclophosphamide can be given to attempt to control inflammation when the kidneys are severely affected. However, the effects of corticosteroids on renal manifestations are not clear.

Key Points
• IgAV is vasculitis that affects primarily small vessels and occurs in children.
• Manifestations can include purpuric rash, arthralgias, fever, abdominal pain, and melena.
• Symptoms usually remit after about 4 wk.
• Diagnose by biopsy.
• Treat symptoms and consider corticosteroids.

CLINICAL VIGNETTES

A mother brings her 5-year-old boy to the clinic because of a rash on his legs and buttocks that she noticed this morning. He has also been complaining that his "belly hurts," but has had no change in appetite. He had an upper respiratory tract infection and sore throat about 1 week ago. He has not had any fevers, recent weight loss or joint pain, and has not taken any medications. His temperature is 37.0 C (98.6 F). Physical examination shows mild periumbilical tenderness and multiple 3-6 mm raised erythematous lesions on his lower extremities and buttocks. The lesions do not blanch with pressure. His leukocyte count, hemoglobin, platelet count, and coagulation studies are normal. Urinalysis shows 3-5 RBCs per hpf. A rapid strep test is positive. The most likely diagnosis is

A. Henoch-Schönlein purpura
B. Idiopathic thrombocytopenic purpura
C. Kawasaki disease
D. Rocky Mountain spotted fever
E. Wiskott-Aldrich syndrome

The correct answer is A. This patient presents with a classic case of Henoch-Schönlein purpura (HSP). HSP is an Ig-A mediated vasculitis involving the small blood vessels (arterioles and venules) of the skin, GI tract, kidneys, and joints. It is the most common vasculitis affecting children. The mean age is 4-7 years of age with slight male predominance. About 50% of children have a preceding upper respiratory tract infection and about 75% have group A strep recovered from their oropharynx. The classic rash is described as palpable purpura concentrated on the buttocks and lower extremities, but rarely on the trunk. These children can also present with non-migratory arthritis, colicky abdominal pain, microscopic or gross hematuria indicative of nephritis, and males can present with scrotal swelling. These patients must have a normal or elevated platelet count. This is what differentiates HSP from idiopathic thrombocytopenic purpura (ITP) (choice B). ITP also presents with a purpuric rash, but these children have low platelet counts. It is thought that these children develop an autoantibody to the platelet surface after a viral illness.

Kawasaki disease (choice C) is also known as mucocutaneous lymph node syndrome. It is an acute febrile vasculitis, which primarily affects the medium-sized vessels with particular affinity to the coronary arteries. Children must meet certain diagnostic criteria to be given the diagnosis of Kawasaki disease. They include fever for at least 5 days, plus four of the following five criteria: bilateral conjunctival injection; injected pharynx/dry or fissured lips/strawberry tongue; edema/erythema of the hands and feet; non-vesicular truncal rash; and cervical lymphadenopathy. The patient in the vignette does not meet the criteria for Kawasaki disease.

Rocky Mountain spotted fever (choice D) is an infectious disease caused by the bacterium Rickettsia rickettsii. These patients will present with fever, headache, malaise, and the classic rash is maculopapular and begins on the extremities and spreads inward to the trunk and includes the palms and soles. The rash may become purpuric after several days.

Wiskott-Aldrich syndrome (choice E) is an X-linked recessive syndrome characterized by eczema, thrombocytopenia, petechiae, and recurrent infections. This presentation is quite different from the boy in this vignette.

A 7-year-old boy arrives at the emergency room in acute distress. Over the past 3 to 4 days he has become progressively ill with generalized fatigue and mild, mid-abdominal pain that have become steadily worse. On physical examination he has a maculopapular rash on his thighs and feet with some spread of the rash to his buttocks. The rash does not blanch and the some lesions near the ankles look petechial or bruised. His temperature is 39.0 C(102.2 F) and he is drawing his knees to his chest for relief of his stomach pains. He is nauseated and vomited once before coming to the hospital. He has semi-soft dark stool, which is guaiac-positive. The boy has not voided since early morning and cannot provide a urine sample. The doctor determines that he is 10% dehydrated and asks the nurse to start intravenous fluids. Which of the following is the most likely diagnosis?

A. Pancreatitis 
B. Rocky Mountain spotted fever 
C. Nephrotic syndrome 
D. Henoch-Schönlein Purpura 
E. Appendicitis 

D. Henoch- Schönlein Purpura (HSP) is the most likely diagnosis. This boy has abdominal pain with guaiac-positive stools, but also has a prominent rash, mostly on his lower extremities. Other characteristic findings of HSP include hematuria and joint pains. The illness may follow an upper respiratory infection or strep throat. The rash starts out as an urticarial rash and progresses to become petechial and purpuric. There may be a history of migratory joint pain and arthritis. Affected joints include ankles, knees, wrists, and elbows.

If the abdominal pain were described as epigastric with radiation to the back, pancreatitis (choice A) might have been the likely diagnosis.In children, pancreatitis is frequently associated with viral illnesses (e.g., mumps), drugs (e.g., sulfonamides), or underlying systemic disease (e.g., lupus). Although pancreatitis has been reported in association with HSP, it is not the most likely diagnosis. 

Rocky Mountain spotted fever (choice B) is one of the most common tick-borne diseases. The typical rash of RMSF appears within a week of the tick bite. It begins on the palms, soles, and extremities and spreads centrally. Severe headache and photophobia are common complaints. 

This child did not have the typical findings of nephrotic syndrome (choice C) including: proteinuria, edema, and oliguria. Nephrotic syndrome frequently follows an infectious illness. 

In the classic case of appendicitis (choice E) periumbilical pain progresses with localization to the right lower quadrant.Anorexia, nausea, vomiting and changes in bowel movements may all occur. Fever is typically low-grade and rash is not present.

A 6-year-old boy is brought to the office by his mother because of a "red rash" that she noticed today. She says that 3 days ago he had a cough, runny nose, and fever that responded to ibuprofen. In the office, his temperature is 37 C (98.6 F) and he has an erythematous, blanching macular rash on his legs. You diagnose him with a viral exanthem and advise the mother to encourage the child to drink liquids and to use ibuprofen as needed for fever. One week later, the mother brings the child back to the office and reports that the rash has "changed", he has developed colicky abdominal pain several times per day, and he is complaining of left knee pain. In the office, his temperature is 37.2 C (99 F), blood pressure is 100/65 mm Hg, pulse is 100/min, and respiratory rate is 15/min. A physical examination reveals palpable purpura of both lower extremities and a soft, non-tender abdomen. His left knee is painful on flexion, but it is not erythematous or warm, and there does not seem to be an effusion. His gait is normal. The most appropriate study at this time is

A. arthrocentesis
B. colonoscopy
C. cultures of blood, urine, and cerebrospinal fluid
D. urinalysis

The correct answer is D. This patient most likely has Henoch-Schonlein purpura (HSP), a small-vessel vasculitis seen most commonly in children between the ages of 2 and 8. The child's preceding upper respiratory tract infection, low-grade fever, and arthralgias are all common elements of this disease. The typical rash of HSP is an evanescent, erythematous, macular rash on the lower extremities that progresses over the course of days to petechiae and palpable purpura. These change in color from red to purple to brown before eventually fading, normally over the course of weeks. HSP is an IgA-mediated autoimmune vasculitis, which can cause tissue damage as a result of immune complex formation. Deposition of these immune complexes in the kidneys can lead to nephritis, which is the leading cause of permanent sequelae from HSP. End-stage renal disease is an uncommon but possible outcome. It is important to perform frequent urinalyses for early detection of kidney involvement.

The joint manifestations of HSP are commonly arthralgias without arthritis, and can last weeks to months. Residual joint disease is rare, and arthrocentesis (choice A) is not necessary as part of the diagnostic evaluation.

Immune complex deposition in the bowel wall can lead to colicky abdominal pain in the setting of HSP and can result in serious, life-threatening sequelae (e.g., intussusception, perforation). This child's abdomen is benign on examination, and his symptoms should be followed clinically. A colonoscopy (choice B) is not necessary at this time.

While petechiae and purpura can be manifestations of overwhelming infection, often due to N. meningitis, the time course of the disease, the well-appearance of the child, and his stable vital signs argue against an infectious cause of this child's symptoms. Thus, cultures from multiple body sites (choice C) are not warranted at this time.
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Hemophilia
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Hemophilias are common hereditary bleeding disorders caused by deficiencies of either clotting factor VIII or IX. The extent of factor deficiency determines the probability and severity of bleeding. Bleeding into deep tissues or joints usually develops within hours of trauma. The diagnosis is suspected in a patient with an elevated PTT and normal PT and platelet count; it is confirmed by specific factor assays. Treatment includes replacement of the deficient factor if acute bleeding is suspected, confirmed, or likely to develop (eg, before surgery).

Hemophilia A (factor VIII deficiency), which affects about 80% of patients with hemophilia, and hemophilia B (factor IX deficiency) have identical clinical manifestations and screening test abnormalities. Both are X-linked genetic disorders. Specific factor assays are required to distinguish the two.

Etiology
Hemophilia is an inherited disorder that results from mutations, deletions, or inversions affecting a factor VIII or factor IX gene. Because these genes are located on the X chromosome, hemophilia affects males almost exclusively. Daughters of men with hemophilia are obligate carriers, but sons are normal. Each son of a carrier has a 50% chance of having hemophilia, and each daughter has a 50% chance of being a carrier.

Pathophysiology
Normal hemostasis requires > 30% of normal factor VIII and IX levels. Most patients with hemophilia have levels < 5%; some have extremely low levels (< 1%). The functional level (activity) of factor VIII or IX in hemophilia A and B, and thus bleeding severity, varies depending on the specific mutation in the factor VIII or IX gene.

Carriers usually have levels of about 50%; rarely, random inactivation of their normal X chromosome in early embryonic life results in a carrier having factor VIII or IX levels of < 30%.

Most patients with hemophilia who were treated in the early 1980s were infected with HIV due to contaminated factor concentrates. Occasional patients developed immune thrombocytopenia secondary to HIV infection, which exacerbated bleeding.

Symptoms and Signs
Patients with hemophilia bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage). The bleeding may be immediate or occur slowly, depending on the extent of trauma and plasma level of factor VIII or IX. Pain often occurs as bleeding commences, sometimes before other signs of bleeding develop. Chronic or recurrent hemarthroses can lead to synovitis and arthropathy. Even a trivial blow to the head can cause intracranial bleeding. Bleeding into the base of the tongue can cause life-threatening airway compression.

Severe hemophilia (factor VIII or IX level < 1% of normal) causes severe bleeding throughout life, usually beginning soon after birth (eg, scalp hematoma after delivery or excessive bleeding after circumcision). Moderate hemophilia (factor levels 1 to 5% of normal) usually causes bleeding after minimal trauma. In mild hemophilia (factor levels 5 to 25% of normal), excessive bleeding may occur after surgery or dental extraction.

Diagnosis
• Platelet count, PT, PTT, factor VIII and IX assays
Sometimes von Willebrand factor activity and antigen and multimer composition

Hemophilia is suspected in patients with recurrent bleeding, unexplained hemarthroses, or a prolongation of the PTT. If hemophilia is suspected, PTT, PT, platelet count, and factor VIII and IX assays are obtained. In hemophilia, the PTT is prolonged, but the PT and platelet count are normal. Factor VIII and IX assays determine the type and severity of the hemophilia.

Prevention
Patients should avoid aspirin and NSAIDs (both inhibit platelet function). Regular dental care is essential so that tooth extractions and other dental surgery can be avoided. Drugs should be given orally or IV; IM injections can cause hematomas. Patients with hemophilia should be vaccinated against hepatitis B.

Treatment
• Replacement of deficient factor
• Sometimes antifibrinolytics

Replacement of the deficient factor is the primary treatment. In hemophilia A, the factor VIII level should be raised.

In hemophilia B, factor IX can be given as a purified or recombinant viral-inactivated product every 24 h. The target levels of factor correction are the same as in hemophilia A.

Fresh frozen plasma contains factors VIII and IX. However, unless plasma exchange is done, sufficient whole plasma usually cannot be given to patients with severe hemophilia to raise factor VIII or IX to levels that prevent or control bleeding. Fresh frozen plasma should, therefore, be used only if rapid replacement therapy is necessary and factor concentrate is unavailable or the patient has a coagulopathy that is not yet defined precisely.

Key Points
• Hemophilias are x-linked recessive disorders of coagulation.
• Hemophilia A (about 80% of patients) involves factor VIII deficiency, and hemophilia B involves factor IX deficiency.
• Patients bleed into tissues (eg, hemarthroses, muscle hematomas, retroperitoneal hemorrhage) following minimal trauma; fatal intracranial hemorrhage may occur.
• The PTT is prolonged but the PT and platelet count are normal; factor VIII and IX assays determine the type and severity of the hemophilia.
• Patients with bleeding or in whom bleeding is anticipated (eg, before surgery or dental extraction) are given replacement factor, preferably using a recombinant product; dose depends on the circumstances.
• About 15 to 35% of patients with hemophilia A develop antibodies to factor VIII.

CLINICAL VIGNETTES

A 4-year old boy was brought to hospital with a swollen right knee. His only sibling, his sister mentioned that when they were playing this morning in the backyard, he jumped down off the slide and immediately complained of pain in his right knee. His mother then recalled that some months ago he bled for an unusually longer time following injury with a razor. The diagnosis of either hemophilia A or B was suspected and he was transfused with fresh plasma and scheduled for measurement of serum levels of factor VIII and factor IX. Awaiting these measurements, which of the following labs values would be consistent with a diagnosis of hemophilia?

A. PTT is prolonged but the PT and platelet count are normal
B. PT is prolonged but the PTT and platelet count are normal
C. PT and PTT are prolonged but platelet count are normal
D. PTT is prolonged and the platelet count is low
E. PT is prolonged and the platelet count is low

Answer is: A

A 5-year-old boy is brought to an emergency room because of a painful, swollen knee joint. The boy had fallen while playing, and the joint had subsequently begun to swell. The mother reports that the boy was known to have hemophilia. Replacement of which of the following is indicated?

A. Factor C 
B. Factor S 
C. Factor VII 
D. Factor VIII 
E. Factor IX 

Answer is E. Hemophilia B is clinically very similar to hemophilia A, but is due to X-linked deficiency of blood clotting factor IX rather than VIII. This patient needs factor IX replacement to stop his bleeding. The method used for calculating the amount of Factor VIII to give in hemophiliac A patients is to multiply the patient's weight in pounds by 20 and then by the desired plasma level in units. If this algorithm is used in hemophiliac B patients to calculate factor IX levels, it is found that the actual achieved blood levels are only about half that expected, possibly because Factor IX tends to bind to the endothelium of the vessel walls. For this reason, it is important to either monitor the patient for cessation of bleeding or check clotting times before assuming that a calculated dose of Factor IX had its intended effect. Aspiration of blood out of a joint (such as in this case) is usually only attempted after the bleeding process is under control. 

Factor C (choice A) deficiency and Factor S (choice B) deficiency cause a thrombotic tendency. 

Factor VII (choice C) deficiency is a rare, autosomal recessive cause of serious bleeding. 

Factor VIII (choice D) deficiency causes hemophilia A. 
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Neurofibromatosis 
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Neurofibromatosis refers to several related disorders that have overlapping clinical manifestations but that are now understood to have distinct genetic causes. It causes various types of benign or malignant tumors that involve central or peripheral nerves and often causes pigmented skin macules and sometimes other manifestations. Diagnosis is clinical. There is no specific treatment, but benign tumors can be removed surgically, and malignant tumors (which are less common) can be treated with radiation therapy or chemotherapy.

There are several types of neurofibromatosis.

Neurofibromatosis type 1 (NF1, or von Recklinghausen disease) is most prevalent, occurring in 1 of 2500 to 3000 people. It causes neurologic, cutaneous, and sometimes soft-tissue or bone manifestations. The gene for NF1 is located on band 17q11.2 and encodes synthesis of neurofibromin; > 1000 mutations have been identified. Although it is an autosomal dominant disorder, 20% to 50% of cases are caused by a de novo germ cell mutation.

Neurofibromatosis type 2 (NF2) accounts for 10% of cases, occurring in about 1 of 35,000 people. It manifests primarily as congenital bilateral acoustic neuromas (vestibular schwannomas). The gene for NF2 is located on band 22q11 and encodes synthesis of merlin, a tumor suppressor; 200 mutations have been identified. Most people with NF2 inherited it from one of their parents.

Tumors may be peripheral or central.

Peripheral tumors are common in NF1 and can develop anywhere along the course of peripheral nerves. The tumors are neurofibromas, which develop from nerve sheaths and consist of mixtures of Schwann cells, fibroblasts, neurial cells, and mast cells. Most appear during adolescence. Occasionally, they transform to malignant peripheral nerve sheath tumors. 

There are multiple forms: cutaneous neurofibromas are soft and fleshy, subcutaneous neurofibromas are firm and nodular. Diffuse plexiform neurofibromas (subcutaneous nodules or amorphous overgrowth of underlying bone or Schwann cells) can be disfiguring and may cause deficits distal to the neurofibroma. These neurofibromas can become malignant.
Schwannomas are derived from Schwann cells, rarely undergo malignant transformation, and can occur in peripheral nerves anywhere in the body.

Central tumors have several forms:

Optic gliomas: These tumors are low-grade pilocytic astrocytomas, which may be asymptomatic or may progress enough to compress the optic nerve and cause blindness. They occur in younger children; these tumors can usually can be identified by age 5 and rarely develop after age 10. They occur in NF1.
Acoustic neuromas (vestibular schwannomas): These tumors may cause dizziness, ataxia, deafness, and tinnitus due to compression of the 8th cranial nerve; they sometimes cause facial weakness due to compression of the adjacent 7th nerve. They are the distinguishing feature of NF2.
Meningiomas: These tumors develop in some people, particularly those with NF2.

Symptoms and Signs
Type 1: Most patients are asymptomatic. Some present with neurologic symptoms or bone deformities. In > 90%, characteristic skin lesions are apparent at birth or develop during infancy. Lesions are medium-brown (café-au-lait), freckle-like macules, distributed most commonly over the trunk, pelvis, and flexor creases of elbows and knees. During late childhood, flesh-colored cutaneous tumors of various sizes and shapes appear, ranging in number from several to thousands. Rarely, plexiform neurofibromas develop, causing an irregularly thickened, distorted structure with grotesque deformities.

Although unaffected children may have 2 or 3 café-au-lait macules, children with NF1 have ≥ 6 such macules and often many more. 

Neurologic symptoms vary, depending on location and number of neurofibromas. Bone abnormalities include 

Fibrous dysplasia
Subperiosteal bone cysts
Vertebral scalloping
Scoliosis
Thinning of the long-bone cortex
Pseudarthrosis
Absence of the greater wing of the sphenoid bone (posterior orbital wall), with consequent pulsating exophthalmos

Type 2: Bilateral acoustic neuromas develop and become symptomatic during childhood or early adulthood. They cause hearing loss, unsteadiness, and sometimes headache or facial weakness. Bilateral 8th cranial (vestibulocochlear) nerve masses may be present. Family members may have gliomas, meningiomas, or schwannomas. 

Diagnosis
• Clinical evaluation
• CT or MRI
Most patients with NF1 are identified during routine examination, examination for cosmetic complaints, or evaluation of a positive family history. Diagnosis of both types is clinical. For the few children who have 3 to 5 café-au-lait macules of > 5 mm diameter, the absence of Lisch nodules on ophthalmologic examination suggests NF1 is not present.

MRI is done in patients with neurologic symptoms or signs and in younger children who meet the clinical criteria for NF1 and who may have an optic glioma when detailed visual testing is not possible. T2-weighted MRI may show optic nerve swelling and parenchymal hyperintense lesions that change over time and correlate with small cystic structures in NF1; MRI may help identify acoustic neuromas or meningiomas in NF2. If acoustic neuroma is suspected, CT of the petrous ridge can be done; it typically shows widening of the auditory canal.

Genetic testing is not typically done in these disorders because not all mutations are known and the clinical criteria are clear.

Treatment
• Possibly surgery or irradiation
No general treatment is available. Neurofibromas that cause severe symptoms may require surgical removal or irradiation, although surgery may obliterate function of the involved nerve. Optic gliomas or CNS lesions that have become malignant may be treated with radiation therapy or chemotherapy.

Genetic counseling is advisable. If either parent has neurofibromatosis, risk to subsequent offspring is 50%; if neither has it, risk for subsequent children is unclear because new mutations are common, particularly in NF1.

Key Points
• There are 2 main types of neurofibromatosis: NF1 and NF2; they are caused by gene mutations.
• NF1 causes cutaneous, neurologic, and bone abnormalities.
• NF2 causes bilateral acoustic neuromas.
• Diagnosis is made using clinical criteria; neuroimaging is done if patients have neurologic abnormalities.
• There is no specific treatment, but neurofibromas that cause severe symptoms may be removed surgically or treated with radiation therapy.

CLINICAL VIGNETTES

An 8-year-old boy presents to the physician for a routine health maintenance visit. His mother states that he has had difficulty reading and concentrating in his second-grade class. On examination, seven café-au-lait spots on his body, as well as two small, soft masses above his orbit, are seen. He also has axillary freckling. His mother also has café-au-lait spots on her arms. Which of the following is the most likely diagnosis? 

A. Congenital hypothyroidism
B. Marfan syndrome
C. Neurofibromatosis
D. Osteogenesis imperfecta
E. Tuberous sclerosis

C. Neurofibromatosis is a multisystem genetic disorder. The features of this condition are more than six café-au-lait spots, two or more neurofibromas, axillary freckling, optic gliomas, iris hamartomas (Lisch nodules), and osseous lesions. There is almost always a first-degree relative with neurofibromatosis. Congenital hypothyroidism (choice A) is associated with poor feeding, an enlarged fontanelle, an enlarged tongue, and an umbilical hernia in the neonatal period. It would not go undetected until 8 years of age. Marfan syndrome (choice B) is a connective tissue disorder characterized by long fingers, hypermobile joints, subluxation of the lenses, pectus carinatum, and aortic aneurysms. Osteogenesis imperfecta (choice D) is a rare connective tissue disease characterized by recurrent fractures, blue sclera, thin skin, and hyperextensibility of ligaments. Tuberous sclerosis (choice E) is associated with facial angiofibromas (adenoma sebaceum), retinal hamartomas, seizures, and mental retardation. Seizures are the most common presenting symptom. It is an autosomal-dominant inherited disease. 

Physical examination of a 14-year-old boy demonstrates six coffee-colored skin macules up to 3 cm in diameter. No other skin lesions are noted, but a small mass lesion is felt in the subcutaneous tissues below two of the macules. These masses are most likely closely associated with which of the following structures?

A. Arrector pili
B. Hair follicles
C. Peripheral nerves
D. Sebaceous glands
E. Sweat glands

The correct answer is C. The lesions are café au lait spots. Isolated café au lait spots are common in the general population, but more than 3 or 4 café au lait spots suggests the possibility of neurofibromatosis. Apparently, the peripheral nerve tumors (neurofibromas) that are part of this syndrome sometimes induce hyperpigmentation of the overlying skin, producing the café au lait spots.

The arrector pili (choice A) are the small muscles of the hair follicle that give rise the sensation of "goose-bumps"; it is thought that some leiomyomas of the skin may arise from these tiny muscles.

Hair follicles (choice B), sebaceous glands (choice D), and sweat glands (choice E) can give rise to a variety of benign and, very rarely, malignant tumors of the skin that do not usually involve subcutaneous tissues.
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Osteogenesis Imperfecta 
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Osteogenesis imperfecta (OI) is a hereditary collagen disorder causing diffuse abnormal fragility of bone and is sometimes accompanied by sensorineural hearing loss, blue sclerae, dentinogenesis imperfecta, and joint hypermobility.

There are 4 main types of OI; types I and IV are autosomal dominant, whereas types II and III are autosomal recessive. Ninety percent of people who have one of the major types have mutations in the genes encoding the pro-alpha chains of procollagen type I, COL1A1 or COL1A2. Other types are rare and are caused by mutations in different genes.

Symptoms and Signs
Hearing loss is present in 50 to 65% of all patients with OI and may occur in any of the 4 types.

Type I is the mildest. Symptoms and signs in some patients are limited to blue sclerae (due to a deficiency in connective tissue allowing the underlying vessels to show through) and musculoskeletal pain due to joint hypermobility. Recurrent fractures in childhood are possible.

Type II (neonatal lethal type or OI congenita) is the most severe and is lethal. Multiple congenital fractures result in shortened extremities. Sclerae are blue. The skull is soft and, when palpated, feels like a bag of bones. Because the skull is soft, trauma during delivery may cause intracranial hemorrhage and stillbirth, or neonates may die suddenly during the first few days or weeks of life.

Type III is the most severe nonlethal form of OI. Patients with type III have short stature, spinal curvature, and multiple, recurrent fractures. Macrocephaly with triangular facies and pectal deformities are common. Scleral hue varies.

Type IV is intermediate in severity. Survival rate is high. Bones fracture easily in childhood before adolescence. Sclera are typically normal in color. Height is moderate-short stature. Accurate diagnosis is important because these patients may benefit from treatment.

Diagnosis
• Clinical evaluation
• Sometimes analysis of type I procollagen or genetic testing
Diagnosis is usually clinical, but there are no standardized criteria. Analysis of type I procollagen (a structural component of bones, ligaments, and tendons) from cultured fibroblasts (from a skin biopsy) or sequence analysis of the COL1A1 and COL1A2 genes can be used when clinical diagnosis is unclear. Severe OI can be detected in utero by level II ultrasonography.

Treatment
• Growth hormone
• Bisphosphonates
Growth hormone helps growth-responsive children (types I and IV). There is limited experience with the use of IV bisphosphonates (eg, pamidronate 0.5 to 3 mg/kg once/day for 3 days, repeated as needed q 4 to 6 mo) with children, but they can increase bone density and decrease bone pain and fracture frequency. Preliminary studies suggest that oral alendronate (1 mg/kg, 20 mg maximum) is also effective. Orthopedic surgery, physical therapy, and occupational therapy help prevent fractures and improve function. Cochlear implantation is indicated in selected cases of hearing loss.


CLINICAL VIGNETTES

A 4-year-old boy is being evaluated for short stature. He has a history of multiple bone fractures in the past. He requires a wheelchair to ambulate and has hearing difficulty. On physical examination, his height is below the 5th percentile. His sclerae are blue in color. There is marked deformity of his lower extremities. Which of the following is the most likely diagnosis? 

A. Achondroplasia
B. Constitutional delay of growth
C. Developmental dysplasia of the hip
D. Familial short stature
E. Osteogenesis imperfecta

E. The boy in this clinical vignette has osteogenesis imperfecta, which is a group of disorders caused by deficiencies in the synthesis of type 1 collagen. Although the hallmark of the disease is prominent skeletal deformity, other anatomic structures rich in type 1 collagen, such as joints, eyes, ears, skin, and teeth, are affected as well. The clinical expression of osteogenesis imperfecta constitutes a spectrum of disorders all marked by extreme skeletal fragility. Four major subtypes have been distinguished. The type II variant is at one end of the spectrum and is uniformly fatal in utero or during the perinatal period. It is characterized by extraordinary bone fragility with multiple fractures occurring when the fetus is still within the womb. In contrast, the type I form, which is more often due to an acquired rather than to a hereditary mutation, permits a normal life span but with an increased number of fractures during childhood. These decrease in frequency after puberty. 

Other findings include blue sclerae caused by a decrease in collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid; hearing loss related to both a sensorineural deficit and impeded conduction owing to abnormalities in the bones of the middle and inner ear; and dental imperfections (small, misshapen, and blue-yellow teeth) secondary to a deficiency of dentin. In type III, the bony deformity is pronounced and not necessarily due to fractures. Mobility is impaired, and most patients require a wheelchair at an early age. Stature may be severely compromised. Because of a progressive vertebral column deformity and rib fractures, restrictive lung disease is a common problem. A basilar impression causing compression of the brainstem and the craniocervical junction can produce central sleep apnea, headache, and upper motor neuron signs. 

Patients with type IV osteogenesis imperfecta generally have reduced stature, some bony deformity, and abnormal teeth that are opalescent and wear easily. The tendency to fracture is highest in childhood and lessens with adolescence. A distinguishing characteristic of type IV is a normal scleral hue. The management of skeletal complications largely depends on orthopedic, physical, and occupational therapy approaches. The long-term goal is to maintain function and independence as an individual. These goals can be advanced in some by judicious use of intramedullary rods in the long bones of the legs. If mobility, especially ambulation, can be maintained, the demineralization associated with inactivity can be avoided. Unaffected parents of a child with osteogenesis imperfecta, as well as all affected individuals, should have genetic counseling. 

Achondroplasia (choice A) is one of the chondrodystrophies that result in disproportionately short stature. Short, tubular bones form because of abnormal endochondral ossification in the limbs. Constitutional delay of growth (choice B) is suggested by a child who is growing at a normal or mildly decreased rate. The patient is delayed in pubertal development, and the bone age significantly lags behind the chronologic age. Developmental dysplasia of the hips (choice C) results from loss of contact between the acetabulum and the head of the femur. Familial short stature (choice D) is characterized by a child with short parents, by a bone age consistent with the chronologic age, and by a growth curve that follows the normal pattern even though it is significantly below the 3rd percentile. 

A family suspected of child abuse because one of their children has had multiple fractures consults an orthopedic specialist at a children's hospital. The specialist examines the child, who is now 5 years old, and notes that the child has blue-tinged sclera, hearing loss, and small, slightly blue, misshapen teeth. Radiologic studies confirm the presence of numerous fractures of various ages. No significant degree of bruising is seen over sites of recent fracture. The disease this child most likely has is related to abnormal metabolism involving which of the following substances?

A. Collagen
B. Glycogen
C. Mucopolysaccharides
D. Purines
E. Tyrosine

The correct answer is A. The suspected disease is osteogenesis imperfecta, which is a rare genetic disorder that occurs in both recessive and dominant forms. The clinical presentation, depending on the specific form, varies from death in utero, to that described in the question stem, to very mild disease with only a modest increase in bone fragility. The different types all have defects in the synthesis of type I collagen, often with insufficient or abnormal pro-alpha chains. These deficits produce an unstable collagen triple helix that is not as strong as normal collagen.

Defective glycogen (choice B) metabolism is associated with the various glycogen storage diseases, such as von Gierke disease and Pompe disease. These diseases tend to present with profound hypoglycemia, hepatomegaly, or muscle weakness.

Defective mucopolysaccharide (choice C) metabolism is associated with the mucopolysaccharidoses, such as Hurler and Hunter syndromes. These diseases tend to present with abnormal facies ("gargoylism"), deformed ("gibbus") back, claw hand, and stiff joints.

Abnormalities of purine metabolism (choice D) are present in gout, which presents with joint inflammation and often involves the great toe.

Abnormalities of tyrosine metabolism (choice E) are associated with phenylketonuria (pale hair and skin, mental retardation, musty smelling urine), albinism (pale hair, skin, increased skin cancer), cretinism (decreased T3 and T4), tyrosinosis (liver and kidney disease), and alkaptonuria (chronic arthritis and urine that turns black upon standing).
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Mitral Valve Prolapse
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Mitral valve prolapse (MVP) is a billowing of mitral valve leaflets into the left atrium during systole. The most common cause is idiopathic myxomatous degeneration. MVP is usually benign, but complications include mitral regurgitation, endocarditis, chordal rupture, and possibly thromboembolism. MVP is usually asymptomatic in the absence of important regurgitation, although there are reports that some patients experience chest pain, dyspnea, dizziness, and palpitations. Signs include a crisp mid-systolic click, followed by a late systolic murmur if regurgitation is present. Diagnosis is by physical examination and echocardiography. Prognosis is excellent in the absence of significant regurgitation, but chordal rupture and endocarditis may occur. No specific treatment is necessary unless significant mitral regurgitation is present.

MVP is common; prevalence is 1 to 3% in otherwise normal populations, depending on the echocardiographic criteria used. Women and men are affected equally; onset usually follows the adolescent growth spurt.

Etiology
MVP is most often caused by

Myxomatous degeneration of the mitral valve leaflets and chordae tendineae
In myxomatous degeneration, the fibrous collagen layer of the valve thins and mucoid (myxomatous) material accumulates. The chordae become longer and thinner and the valve leaflets enlarge and become rubbery. These changes result in floppy valve leaflets that can balloon back (prolapse) into the left atrium when the left ventricle contracts. Rupture of a degenerate chorda can allow part of the valve leaflet to flail into the atrium, which typically causes severe regurgitation.

Degeneration is usually idiopathic, although it may be inherited in an autosomal dominant or, rarely, in an X-linked recessive fashion. Myxomatous degeneration may also be caused by connective tissue disorders (eg, Marfan syndrome, Ehlers-Danlos syndrome, adult polycystic kidney disease, osteogenesis imperfecta, pseudoxanthoma elasticum, SLE, polyarteritis nodosa) and muscular dystrophies. MVP is more common among patients with Graves disease, hypomastia, von Willebrand syndrome, sickle cell disease, and rheumatic heart disease. Myxomatous degeneration may also affect the aortic or tricuspid valve, resulting in aortic or tricuspid prolapse. Primary tricuspid regurgitation is much less common than secondary tricuspid regurgitation due to mitral regurgitation (MR).

MR due to MVP may occur in patients with apparently normal mitral valve leaflets (ie, nonmyxomatous) due to papillary muscle dysfunction or rheumatic chordal rupture. Transient MVP may occur when intravascular volume decreases significantly, as occurs in severe dehydration or sometimes during pregnancy (when the woman is recumbent and the gravid uterus compresses the inferior vena cava, reducing venous return).

Complications: MR is the most common complication of MVP. MR may be acute (due to ruptured chordae tendineae causing flail mitral valve leaflets) or chronic. Sequelae of MVP with MR include heart failure, infective endocarditis, and atrial fibrillation (AF) with thromboembolism. Whether MVP causes stroke or endocarditis independent of MR and AF is unclear. 

Symptoms and Signs
Most patients are asymptomatic. Some experience nonspecific symptoms (eg, chest pain, dyspnea, palpitations, dizziness, near syncope, migraines, anxiety) thought to be due to poorly defined associated abnormalities in adrenergic signaling and sensitivity rather than to mitral valve pathology. In about one third of patients, emotional stress precipitates palpitations, which may be a symptom of benign arrhythmias (atrial premature beats, paroxysmal atrial tachycardia, ventricular premature beats, complex ventricular ectopy).

Occasionally, patients present with MR. Rarely, patients present with endocarditis (eg, fever, weight loss, thromboembolic phenomena) or stroke. Sudden death occurs in < 1%, most often resulting from ruptured chordae tendineae and flail mitral valve leaflets. Death due to a ventricular arrhythmia is rare.

Typically, MVP causes no visible or palpable cardiac signs. MVP alone often causes a crisp mid-systolic click as the subvalve apparatus abruptly tightens. The click is heard best with the diaphragm of the stethoscope over the left apex when the patient is in the left lateral decubitus position. MVP with MR causes a click with a late-systolic MR murmur. 

The click moves closer to the 1st heart sound (S1) with maneuvers that decrease left ventricle (LV) size (eg, sitting, standing, Valsalva maneuver); the same maneuvers cause an MR murmur to appear or become louder and last longer. These effects occur because decreasing LV size causes papillary muscles and chordae tendineae to pull together more centrally beneath the valve, resulting in quicker, more forceful prolapse with earlier, more severe regurgitation. 

Conversely, squatting or isometric handgrip delays the S1 click and shortens the MR murmur. The systolic click may be confused with the click of congenital aortic stenosis; the latter may be distinguished because it occurs very early in systole and does not move with postural or LV volume changes. Other findings include a systolic honk or whoop, thought to be caused by valvular leaflet vibration; these findings are usually transient and may vary with respiratory phase.

Other physical findings associated with but not diagnostic of MVP include hypomastia, pectus excavatum, straight back syndrome, and a narrow anteroposterior chest diameter.

Diagnosis
Echocardiography
Diagnosis is suggested clinically and confirmed by echocardiography. Thickened (≥ 5 mm), redundant mitral valve leaflets are thought to indicate more extensive myxomatous degeneration and greater risk of endocarditis and MR.

Prognosis
MVP is usually benign, but severe myxomatous degeneration of the valve can lead to MR. In patients with severe MR, incidence of LV or left atrium enlargement, arrhythmias (eg, AF), infective endocarditis, stroke, need for valve replacement, and death is about 2 to 4%/yr. Men are less likely to have MVP, but those who do are more likely to progress to severe MR.

Treatment
• Usually none
• Sometimes β-blockers
MVP does not usually require treatment. β-Blockers may be used to relieve symptoms of excess sympathetic tone (eg, palpitations, migraines, dizziness) and to reduce risk of tachyarrhythmias, although no data support this practice. A typical regimen is atenolol 25 to 50 mg po once/day or propranolol 20 to 40 mg po bid.

Treatment of MR depends on severity and associated left atrial and LV changes.

Antibiotic prophylaxis against endocarditis is no longer recommended. Anticoagulants to prevent thromboembolism are recommended only for patients with AF or prior transient ischemic attack or stroke.

Key Points
• MVP is most often caused by idiopathic myxomatous degeneration of the mitral valve and chordae tendineae.
• Mitral regurgitation (MR) is the most common complication.
• Heart sounds often include a sharp, mid-systolic click that occurs earlier with the Valsalva maneuver.
• Prognosis is usually benign unless MR develops, in which case there is increased risk of heart failure, atrial fibrillation, stroke, and infective endocarditis,
• Treatment is not needed unless significant MR develops.

CLINICAL VIGNETTES

A 15-year-old girl presents to a pediatric cardiology clinic with a complaint of chest pain. She states the pain has come and gone over the past year, but has increased in frequency over the past few weeks. She describes it as a sharp pain over her left chest. Physical examination reveals a healthy-appearing 15-year-old girl. Her temperature is 37.2 C (99 F), pulse is 90/min, and respiratory rate is 20/min. Lung examination is normal. Cardiac examination reveals a late systolic murmur preceded by a click at the apex. No heave or rub is present. An electrocardiogram and chest x-ray film are unremarkable. Which of the following is the most likely diagnosis? 

A. Atrial septal defect
B. Mitral regurgitation
C. Mitral stenosis
D. Mitral valve prolapse
E. Tricuspid regurgitation

D. An apical click followed by a late systolic murmur is classic for mitral valve prolapse. It can be a source of subjective chest pain in children. Mitral valve prolapse is more common in females. Antibiotic prophylaxis is recommended prior to dental procedures. An atrial septal defect (choice A) is characterized by a fixed and widely split second heart sound. Mitral (choice B) and tricuspid regurgitation (choice E) produce holosystolic murmurs with relatively uniform intensity. Mitral regurgitation is heard at the apex while tricuspid regurgitation is best heard along the lower left sternal border. Mitral stenosis (choice C) is characterized by a mid-diastolic murmur heard after an opening snap.

A 45-year-old man presents for a routine physical exam as part of an insurance medical assessment. He is asymptomatic and has no family history of cardiac disease or sudden cardiac death. On examination, he is of slim build. BP is 115/65 mmHg, and heart rate 60 bpm and regular. On cardiac exam, apex beat is of normal character and nondisplaced. On auscultation, he has a midsystolic click followed by a late-systolic high-pitched murmur. On standing and with Valsalva maneuver, the click and murmur occur earlier in systole and the murmur is of increased intensity. On squatting, the click and murmur occur later in systole and the murmur is softer in intensity. There are no clinical signs of heart failure. You advise him that if he were to develop symptoms, the best drug treatment for his cardiac condition would be

A) quinidine
B) propranolol
C) digoxin
D) procainamide
E) phenytoin

ANSWER: B. This patient most likely has asymptomatic mitral valve prolapse. The primary treatment for symptomatic mitral valve prolapse is beta-blockers. Symptoms of mitral valve prolapse include chest pain, dyspnea, palpitations, dizziness, near syncope, migraines, and anxiety.

Beta-Blockers may be used to relieve symptoms of excess sympathetic tone (eg, palpitations, migraines, dizziness) and to reduce risk of tachyarrhythmias.

Quinidine and digoxin were used to treat this problem in the past, especially if sinus bradycardia or cardiac arrest occurred with administration of propranolol. Procainamide and phenytoin have not been used to treat this syndrome. 

Asymptomatic patients require only routine monitoring, while those with significant mitral regurgitation may require surgery. Some patients with palpitations can be managed with lifestyle changes such as elimination of caffeine and alcohol. 
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Phenylketonuria (PKU) 
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Phenylketonuria (PKU) is a clinical syndrome of intellectual disability with cognitive and behavioral abnormalities caused by elevated serum phenylalanine. The primary cause is deficient phenylalanine hydroxylase activity. Diagnosis is by detecting high phenylalanine levels and normal or low tyrosine levels. Treatment is lifelong dietary phenylalanine restriction. Prognosis is excellent with treatment.

Inheritance is autosomal recessive; incidence is about 1/10,000 births among whites.

Pathophysiology
Excess dietary phenylalanine (ie, that not used for protein synthesis) is normally converted to tyrosine by phenylalanine hydroxylase. When one of several gene mutations results in deficiency or absence of phenylalanine hydroxylase, dietary phenylalanine accumulates; the brain is the main organ affected, possibly due to disturbance of myelination. Some of the excess phenylalanine is metabolized to phenylketones, which are excreted in the urine, giving rise to the term phenylketonuria. The degree of enzyme deficiency, and hence severity of hyperphenylalaninemia, varies among patients depending on the specific mutation.

Symptoms and Signs
Most children are normal at birth but develop symptoms and signs slowly over several months as phenylalanine accumulates. The hallmark of untreated PKU is severe intellectual disability. Children also manifest extreme hyperactivity, gait disturbance, and psychoses and often exhibit an unpleasant, mousy body odor caused by phenylacetic acid (a breakdown product of phenylalanine) in urine and sweat. Children also tend to have a lighter skin, hair, and eye color than unaffected family members, and some may develop a rash similar to infantile eczema.

Diagnosis
• Routine neonatal screening
• Phenylalanine levels
In many developed countries, all neonates are screened for PKU 24 to 48 h after birth with one of several blood tests; abnormal results are confirmed by directly measuring phenylalanine levels. In classic PKU, neonates often have phenylalanine levels > 20 mg/dL (1.2 mM/L). Those with partial deficiencies typically have levels < 8 to 10 mg/dL while on a normal diet (levels > 6 mg/dL require treatment); distinction from classic PKU requires a liver phenylalanine hydroxylase activity assay showing activity between 5% and 15% of normal or a mutation analysis identifying mild mutations in the gene.

Children in families with a positive family history can be diagnosed prenatally by using direct mutation studies after chorionic villus sampling or amniocentesis.

Prognosis
Adequate treatment begun in the first days of life prevents all manifestations of disease. Treatment begun after 2 to 3 yr may be effective only in controlling the extreme hyperactivity and intractable seizures. Children born to mothers with poorly controlled PKU (ie, they have high phenylalanine levels) during pregnancy are at high risk of microcephaly and developmental deficit.

Treatment
• Dietary phenylalanine restriction
Treatment is lifelong dietary phenylalanine restriction. All natural protein contains about 4% phenylalanine. Therefore dietary staples include low-protein natural foods (eg, fruits, vegetables, certain cereals), protein hydrolysates treated to remove phenylalanine, and phenylalanine-free elemental amino acid mixtures. Some phenylalanine is required for growth and metabolism; this requirement is met by measured quantities of natural protein from milk or low-protein foods.

Frequent monitoring of plasma phenylalanine levels is required; recommended targets are between 2 mg/dL and 4 mg/dL (120 to 240μmol/L) for children < 12 yr and between 2 mg/dL and 10 mg/dL (120 to 600 μmol/L) for children > 12 yr. Dietary planning and management need to be initiated in women of childbearing age before pregnancy to ensure a good outcome for the child. Tyrosine supplementation is increasingly used because it is an essential amino acid in patients with PKU.

CLINICAL VIGNETTES

A newborn infant is noted to have microcephaly after birth. His mother is 38 years old. She also has a 5-year-old son who is mentally retarded and she had one previous second-trimester miscarriage. In addition, she has a genetic disease that required a special diet, but she discontinued the diet many years ago. On physical examination, the infant's weight and length are both below the 10th percentile for his gestational age. He is also noted to have a grade III systolic ejection murmur best heard at the lower left sternal border. Which of the following conditions does the mother most likely have?

A. Galactosemia 
B. Hypothyroidism 
C. Maple syrup urine disease 
D. Phenylketonuria 

D. The mother had phenylketonuria (PKU) early in her life. Many clinically normal female PKU patients, who were treated with diet early in life, discontinue dietary treatment and have marked hyperphenylalaninemia by the time they reach childbearing age. Most children born to such women are mentally retarded and microcephalic, and 15% have congenital heart disease, even though the infants themselves are heterozygotes. This syndrome, known as maternal PKU, results from the teratogenic effects of phenylalanine or its metabolites (which cross the placenta), affecting specific fetal organs during development. It is very important that maternal dietary restriction of phenylalanine is initiated before conception and continues throughout the pregnancy.

The biochemical abnormality in PKU is an inability to convert phenylalanine into tyrosine. With a block in the phenylalanine metabolism secondary to lack of phenylalanine hydroxylase, minor shunt pathways come into play. This produces metabolites, which are excreted in large amounts in the urine in PKU. Some of these abnormal metabolites are excreted in the sweat, and phenylacetic acid, in particular, imparts a strong musty or mousy odor to affected infants. It is proposed that excess phenylalanine or its metabolites contribute to the brain damage and mental retardation in PKU.

Homozygotes with this autosomal recessive disorder classically have a severe lack of phenylalanine hydroxylase, leading to hyperphenylalaninemia and PKU. Affected infants are normal at birth but, within a few weeks, develop a rising plasma phenylalanine level, which in some way impairs brain development. Usually by 6 months of life, severe mental retardation becomes evident. Seizures, other neurologic abnormalities, decreased pigmentation of hair and skin, and eczema often accompany the mental retardation in untreated children. Hyperphenylalaninemia and the resultant mental retardation can be avoided by restricting phenylalanine intake early in life. Hence, a number of screening procedures are routinely used for detection of PKU in the immediate postnatal period.

Galactosemia (choice A) is an autosomal recessive disorder of galactose metabolism that causes significant damage to the liver, eyes, and brain. 

Congenital hypothyroidism (choice B) is associated with cretinism and severe mental retardation. It occurs in 1 in 7000 births and is amenable to in utero diagnosis and treatment. 

Maple syrup urine disease (choice C) is a familial cerebral degenerative disease caused by a defect in branched chain amino acid metabolism and characterized by severe mental and motor retardation and urine with a maple-syrup-like odor. 

A 20-year old female who is 2 months pregnant remembers that she had phenylketonuria (PKU) as a child and required a special diet. Tests confirm markedly elevated maternal serum levels of phenylalanine and phenyl acetic acid. Genetic studies have not been performed on the father. What should the physician tell the parents regarding the welfare of the child? 

A. Childhood phenylalanine restriction is sufficient to protect the health of her child.
B. Further information is required to ascertain if the fetus is at risk.
C. The fetus is at no health risk if it is heterozygous for the PKU gene.
D. The fetus is at no health risk if phenylalanine levels are normalized by the third trimester.
E. The mother's hyperphenylalaninemia may have already harmed the fetus.

The correct answer is E. Phenylalanine crosses the placenta and, if maternal serum levels are elevated, acts as a teratogen to the developing fetus. This condition is known as maternal PKU. Although the mother can fare well with substantial elevations in serum phenylalanine concentration, the children born to such women are usually profoundly retarded and may have multiple birth defects. 

Although dietary modifications (choice A) can prevent the neurological and dermatologic manifestations of PKU in a child, the fetus is still at risk from maternal PKU. 

Further information regarding the cause of this woman's hyperphenylalaninemia (choice B) is not needed, since the fetus is exposed to teratogenic levels of phenylalanine. 

Children born to mothers with untreated PKU develop maternal PKU even if they are heterozygous for the PKU gene (choice C). Fetal phenylalanine hydroxylase cannot compensate for the high maternal levels of phenylalanine.

The critical period in development during which teratogenic materials affect the growing organs is between the 3rd and 8th weeks of gestation. By the end of the 2nd month (compare with choice D), the damage caused by the maternal PKU has already occurred. 
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Ataxia-Telangiectasia 
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Ataxia-telangiectasia results from a DNA repair defect that frequently results in humoral and cellular deficiency; it causes progressive cerebellar ataxia, oculocutaneous telangiectasias, and recurrent sinopulmonary infections.

Inheritance is autosomal-recessive. Estimated incidence is 1 in 20,000 to 100,000 births. Ataxia-telangiectasia is caused by mutations in the gene that encodes ataxia-telangiectasia–mutated (ATM) protein. ATM is involved in detection of DNA damage and helps control the rate of cell growth and division. Patients often lack IgA and IgE and have a progressive T-cell defect.

Symptoms and Signs
Age at onset of neurologic symptoms and evidence of immunodeficiency vary.

Ataxia is frequently the first symptom and usually develops when children begin to walk. Progression of neurologic symptoms leads to severe disability. Speech becomes slurred, choreoathetoid movements and nystagmus develop, and muscle weakness usually progresses to muscle atrophy.

Telangiectasias are widely open (dilated) blood vessels.

Telangiectasias may not appear until age 4 to 6 yr; they are most prominent on the bulbar conjunctivae, ears, antecubital and popliteal fossae, and sides of the neck.

Recurrent sinopulmonary infections lead to recurrent pneumonia, bronchiectasis, and chronic restrictive pulmonary disease.

Certain endocrine abnormalities (eg, gonadal dysgenesis, testicular atrophy, diabetes mellitus) may occur.

Frequency of cancer (especially leukemia, lymphoma, brain tumors, and gastric cancer) is high. Cancer typically occurs after age 10 and at a rate of about 1%/yr but is a lifelong risk and can occur at any age.

Diagnosis
• IgA and serum α1-fetoprotein levels
• Genetic testing

Clinical findings of cerebellar ataxia (particularly when telangiectasias are present), low levels of IgA (present in 80% of patients with this disorder), and high levels of serum α1-fetoprotein suggest the diagnosis. If karyotype analysis is done, chromosome breaks, consistent with a defect in DNA repair, are often seen. Diagnosis is confirmed by identifying mutations on both alleles of the gene for ATM protein. Because carriers of an AT mutation usually remain asymptomatic, testing siblings for a carrier state can help predict their chance of having an affected child.

Testing for endocrine abnormalities and cancers is done based on clinical presentation.

Treatment
Supportive care using prophylactic antibiotics or IV immune globulin
Treatment with prophylactic antibiotics or IV immune globulin may help. In one small study, treatment with amantadine resulted in minimal improvement in motor function, but there is no effective treatment for the progressive neurologic deterioration, which causes death, usually by age 30.

Chemotherapy is often indicated for treatment of associated cancers.

CLINICAL VIGNETTES

A 4-year-old girl is brought to the office by her mother because of skin lesions on the face and arms. She recently noticed them, first on the eyeballs and then on the cheeks and in the elbow crease in increasing numbers. They do not appear to bother the patient. The child's medical history is significant for a gait disorder that began when she started to walk and progressively worsened, and for recurrent sinopulmonary and skin infections. She now has an awkward, swaying gait with choreic and athetoid movements. On examination, there are multiple nonblanching, dilated blood vessels present on the bulbar conjunctivas, on the nose and cheeks, and in the antecubital fossae. The child is drooling and has erythematous, scaly patches with thick purulent crusts on the comers of the mouth. Which or the following is the most likely diagnosis?

A. Ataxia-telangiectasia
B. Chronic granulomatous disease 
C. IgA deficiency
D. Sex-linked agammaglobulinemia
E. Thymic hypoplasia

The correct answer is A . This patient has ataxia-telangiectasia, a syndrome that consists of ataxia, telangiectasia of the eyes and skin, chronic sinopulmonary disease, and endocrine abnormalities. The syndrome is transmitted as an autosomal recessive trait with a defect in the ATM gene located at chromosome 11q22-23. The defective gene codes for a protein kinase. Cerebellar ataxia is the first neurologic sign that most commonly manifests as the patient starts walking. An awkward swaying gait develops, followed by choreic and athetoid movements that worsen with time. Commonly, there are recurrent sinopulmonary infections, impetigo (erythematous, scaly patches with thick purulent crusts), herpetic gingivostomatitis, and lipoatrophy. On physical examination, the patient has a masklike facies with drooling, abnormal eye movements and tics. lgA, lgE, and lgM levels are low. CD3+ and CD4+ T cells are moderately reduced, with moderate or increased numbers of CDS+ T cells. Both the T and B cells are defective. Persistently elevated levels of alpha-fetoprotein and carcinoembryonic antigen occur and may help in early diagnosis of disease. Children are usually confined to a wheelchair by the age of 12. Severe pulmonary infections and bronchiectases complicate the clinical course. Lymphoid malignancies develop in approximately 30% of patients and are the most common cause of death.

A 4-year-old child is evaluated by a neurologist because of difficulty walking. Neurological examination documents ataxia and mental retardation. The neurologist notes the presence of multiple telangiectasias involving the conjunctiva, ears, and antecubital fossae. The child also has a history of multiple respiratory tract infections. Immunoglobulin studies on the child would most likely demonstrate an absence of which of the following?

A. IgA and IgE 
B. IgA and IgG 
C. IgE and IgG 
D. IgE and IgM 
E. IgM and IgG 

A. The child's condition is the autosomal recessive disease, ataxia-telangiectasia, which is a multisystem disorder of unknown etiology. The ataxia is noticed in early childhood, and with time, progresses to severe disability. Choreoathetoid movements, slurred speech, ophthalmoplegia, and progressive mental retardation characterize the disease at it advances. Telangiectasias, as described in the question stem, are a helpful diagnostic clue. These children also are vulnerable recurrent sinopulmonary infections. Immunologic evaluation may demonstrate a lack of IgA and IgE, cutaneous anergy, and a progressive cellular immune defect. Other features of the syndrome include endocrine disorders and a predisposition for certain cancers (leukemias, brain cancer, and gastric cancer). Most of these patients die of their neurologic deterioration by age 30. 

IgG (choices B, C, and E) and IgM (choices D and E) are not specifically affected in this condition. 
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Patent Ductus Arteriosus 
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Patent ductus arteriosus (PDA) is a persistence of the fetal connection (ductus arteriosus) between the aorta and pulmonary artery after birth, resulting in a left-to-right shunt. Symptoms may include failure to thrive, poor feeding, tachycardia, and tachypnea. A continuous murmur at the upper left sternal border is common. Diagnosis is by echocardiography. Administration of indomethacin with or without fluid restriction may be tried in premature infants with a significant shunt, but this therapy is not effective in term infants or older children with PDA. If the connection persists, surgical or catheter-based correction is indicated.

PDA accounts for 5 to 10% of congenital heart anomalies; the male:female ratio is 1:3. PDA is very common among premature infants (present in about 45% with birth weight < 1750 g and in about 80% with birth weight < 1200 g).

Pathophysiology
The ductus arteriosus is a normal connection between the pulmonary artery and aorta; it is necessary for proper fetal circulation. At birth, the rise in Pao2 and decline in prostaglandin concentration cause closure of the ductus arteriosus, typically beginning within the first 10 to 15 h of life. If this normal process does not occur, PDA results.

Physiologic consequences depend on ductal size. A small ductus rarely causes symptoms. A large ductus causes a large left-to-right shunt. Over time, a large shunt results in left heart enlargement, pulmonary artery hypertension, and elevated pulmonary vascular resistance, ultimately leading to Eisenmenger syndrome.

Symptoms and Signs
Clinical presentation depends on PDA size and gestational age at delivery. Infants and children with a small PDA are generally asymptomatic; infants with a large PDA present with signs of HF (eg, failure to thrive, poor feeding, tachypnea, dyspnea with feeding, tachycardia). Premature infants may present with respiratory distress, apnea, worsening mechanical ventilation requirements, or other serious complications (eg, necrotizing enterocolitis). Signs of HF occur earlier in premature infants than in full-term infants and may be more severe. A large ductal shunt in a premature infant often is a major contributor to the severity of the lung disease of prematurity.

Most children with a small PDA have normal heart sounds and peripheral pulses. A grade 1 to 3/6 continuous murmur is heard best in the upper left sternal border. The murmur extends from systole to beyond the 2nd heart sound (S2) into diastole and typically has a different pitch in systole and diastole.

Full-term infants with a significant PDA shunt have full or bounding peripheral pulses with a wide pulse pressure. A grade 1 to 4/6 continuous murmur is characteristic. If the murmur is loud, it has a “machinery-sounding” quality. An apical diastolic rumble (due to high flow across the mitral valve) or gallop rhythm may be audible if there is a large left-to-right shunt or HF develops.

Premature infants with a significant shunt have bounding pulses and a hyperdynamic precordium. A heart murmur occurs in the pulmonary area; the murmur may be continuous, systolic with a short diastolic component, or only systolic, depending on the pulmonary artery pressure. Some infants have no audible heart murmur.

Diagnosis
Chest x-ray and ECG
Echocardiography
Diagnosis is suggested by clinical examination, supported by chest x-ray and ECG, and established by 2-dimensional echocardiography with color flow and Doppler studies.

Chest x-ray and ECG are typically normal if the PDA is small. If the shunt is significant, chest x-ray shows prominence of the left atrium, left ventricle, and ascending aorta and increased pulmonary vascular markings; ECG may show left ventricular hypertrophy. Cardiac catheterization is not necessary unless used for therapy.

Treatment
• Prostaglandin synthesis inhibitor therapy (eg, indomethacin, ibuprofen)
• Sometimes transcatheter occlusion devices or surgical repair
In premature infants with compromised respiratory status, the PDA can sometimes be closed by using a prostaglandin synthesis inhibitor (eg, indomethacin. Three doses of indomethacin are given IV q 12 to 24 h based on urine output; doses are withheld if urine output is < 0.6 mL/kg/h. An alternative is ibuprofen 10 mg/kg po followed by 2 doses of 5 mg/kg at 24-h intervals). Fluid restriction may facilitate ductal closure. In the past, if this treatment was unsuccessful, the PDA was ligated surgically. However, current data do not show improved long-term outcome after surgical intervention, but experts are evaluating whether there are subgroups of patients in whom surgery might be beneficial. In premature infants without respiratory compromise, a PDA is generally not treated.

In full-term infants,indomethacin is usually ineffective. Transcatheter closure has become the treatment of choice in children > 1 yr; a variety of catheter-delivered occlusion devices are available. In infants < 1 yr or who have certain anatomic varieties of the ductus, surgical division and ligation may be preferred over the transcatheter approach. For a PDA with a shunt large enough to cause symptoms of HF or pulmonary hypertension, closure should be done after medical stabilization. For a persistent PDA without HF or pulmonary hypertension, closure can be done electively any time after 1 yr. Outcomes after PDA closure are excellent.

Key Points
• Patent ductus arteriosus (PDA) is a persistence after birth of the normal fetal connection (ductusarteriosus) between the aorta and pulmonary artery, resulting in a left-to-right shunt.
• Manifestations depend on the size of the PDA and the degree of prematurity, but a continuous murmur is characteristic and, if loud, has a “machinery-sounding” quality.
Premature infants may have respiratory distress or other serious complications (eg, necrotizing enterocolitis).
• Over time, a large shunt causes left heart enlargement, pulmonary artery hypertension, and elevated pulmonary vascular resistance, ultimately leading to Eisenmenger syndrome.
• Give premature infants a prostaglandin inhibitor (eg, indomethacin) to close the PDA; surgical closure has not been shown to improve outcomes.
• Prostaglandin inhibitors are usually ineffective in full-term infants, but catheter-delivered occlusion devices or surgery is typically beneficial.

CLINICAL VIGNETTES

A pediatrician examines a 2-month-old infant who had been born at term. The pediatrician hears a continuous murmur at the upper left sternal border. The peripheral pulses in all extremities are full and show widened pulse pressure. Which of the following is the most likely diagnosis?

A. Coarctation of the aorta 
B. Patent ductus arteriosus 
C. Peripheral pulmonic stenosis 
D. Persistent truncus arteriosus 
E. Ventricular septal defect 

B. This is patent ductus arteriosus, which is a failure of closure of the duct between the pulmonary artery and the aorta. As many as 80% of significantly premature (<28 week gestation) infants have patent ductus arteriosus. In term infants, delayed closure is diagnosed if the murmur of the patent ductus (described in the question stem) is still present at 6-8 weeks of age. Infants should be evaluated for other cardiac disease, since a patent ductus arteriosus may be partially compensating for other cardiac anomalies. Infants with heart failure require prompt surgical correction. Infants without heart failure or complicating cardiac defects typically undergo elective surgery at 6 months to 3 years to reduce the risk of infective endarteritis later involving the patent ductus. 

Coarctation of the aorta (choice A) will cause diminished pulses in the legs and sometimes arms. 

Peripheral pulmonic stenosis (choice C) causes murmurs heard over the lung fields. 

Persistent truncus arteriosus (choice D) is a failure of the aorta to separate from the pulmonary artery, and causes heart failure within days to weeks of birth. 

Ventricular septal defect (choice E) causes a murmur heard best at the lower left sternal border. 

During cardiac examination of a newborn infant, a murmur is detected, and the diagnosis of patent ductus arteriosus is made. Which of the following best describes the direction of blood flow through the patent ductus arteriosus in this infant?

A. From aorta to left pulmonary artery
B. From aorta to left pulmonary vein
C. From aorta to right pulmonary artery
D. From left pulmonary artery to aorta
E. From right pulmonary artery to aorta

The correct answer is A. The ductus arteriosus connects the left pulmonary artery to the aortic arch. It is derived from the left sixth aortic arch. During prenatal life, the pressure gradient causes blood to flow from the left pulmonary artery to the aorta. However, after birth, the pressure gradient reverses, and if the ductus arteriosus remains patent, the flow is from the aorta to the left pulmonary artery.

The ductus arteriosus does not connect to the pulmonary veins or the right pulmonary artery (choices B, C, and E).

The flow through the ductus arteriosus is from the left pulmonary artery to the aorta (choice D) prior to birth, but reverses after birth.

Patency of the ductus arteriosus can be artificially prolonged after birth by administration of

A. glucocorticoids
B. indomethacin
C. insulin
D. oxytocin
E. prostaglandins

The correct answer is E. The ductus arteriosus is an arterial channel connecting the aorta with the pulmonary trunk during intrauterine life. Closure of this embryonal vessel occurs in the first few days after birth. Patency of the ductus is maintained by prostaglandins, more specifically prostaglandin E. Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin (choice B), promote closure of this structure since NSAIDs inhibit prostaglandin synthesis. Prostaglandin E and NSAIDs can be used therapeutically to maintain a patent ductus arteriosus or to promote its closure. 

Glucocorticoids (choice A) can accelerate pulmonary maturation and stimulate production of surfactant, but do not affect the ductus arteriosus.

Insulin (choice C) inhibits surfactant production, but has no effect on the ductus arteriosus.

Oxytocin (choice D) is a hypothalamic hormone that stimulates contraction of smooth muscle in the uterus and mammary glands. It has no effect on the ductus arteriosus.

A cyanotic infant is discovered to have a ventricular septal defect, an overriding aorta, right ventricular hypertrophy, and complete pulmonic stenosis. Which of the following accompanying congenital anomalies permits survival in this patient?

A. Bicuspid aortic valve 
B. Ostium secundum defect
C. Patent ductus arteriosus
D. Patent foramen ovale
E. Preductal coarctation of aorta 

The correct answer is C. The ductus arteriosus connects the aorta with the pulmonary artery. If it remains patent after birth, it allows oxygenated blood to flow from the aorta to the pulmonary artery. In this patient with tetralogy of Fallot with complete right ventricular outflow obstruction, this anastomosis is a crucial source of blood to the pulmonary vasculature. 

A bicuspid aortic valve (choice A) may be asymptomatic but can lead to infective endocarditis, left ventricular overload, and sudden death. It is a common cause of aortic stenosis. It would not benefit a patient with tetralogy of Fallot in any way. 

Ostium secundum defect (choice B) is the most common form of atrial septal defect (ASD). ASD is an acyanotic congenital heart disease that would not improve cardiovascular function in a patient with tetralogy of Fallot. 

A patent foramen ovale (choice D) is a slit-like remnant of communication between the left and right atria in the fetus. It is usually not of clinical significance. 

A preductal coarctation of the aorta (choice E) involves narrowing of the aorta proximal to the opening of the ductus arteriosus. This would prevent adequate blood flow through a possible life-preserving PDA and would result in the patient's demise.

An x-ray performed on a newborn infant shows enlargement of the left ventricle and left atrium as well as dilatation of the aorta. Echocardiographic studies demonstrate volume-overloading of the left ventricle. Cardiac auscultation reveals the presence of a continuous "machinery" murmur. Which of the following is the most likely diagnosis?

A. Atrial septal defect
B. Patent ductus arteriosus
C. Pulmonic stenosis
D. Tetralogy of Fallot
E. Ventricular septal defect

The correct answer is B. Patent ductus arteriosus (PDA) is a congenital cardiac disorder in which blood traveling in the aorta is shunted through the ductus arteriosus to the pulmonary arteries. On x-ray, the left ventricle and left atrium may be enlarged, and pulmonary hypertension may be observed. PDA is characterized by a continuous "machinery" murmur on auscultation. If the ductus is widely patent, pulmonary hypertension may eventually develop, and the initially left-to-right shunt is reversed, sending deoxygenated blood through the descending aorta, and producing cyanosis (Eisenmenger syndrome). Since the deoxygenated blood enters the descending aorta, the toes can be cyanotic, but the fingers are generally not.

In atrial septal defect (choice A), left-to-right shunting causes volume overloading of the right ventricle, the increased flow across the pulmonic valve producing a midsystolic pulmonary ejection murmur. The second heart sound is widely split. A diastolic murmur may also be heard, reflecting increased flow from the right atrium into the right ventricle.

Pulmonic stenosis (choice C) typically produces a harsh systolic ejection murmur best heard at the upper left sternal border, often preceded by a systolic ejection sound.

Tetralogy of Fallot (choice D) is a form of cyanotic congenital heart disease characterized by ventricular septal defect, right ventricular outflow tract obstruction, an overriding aorta, and right ventricular hypertrophy. The heart is often described as "boot-shaped" on chest x-ray.

A ventricular septal defect (choice E) would produce an initial left-to-right shunt, characterized by a holosystolic murmur, and increased pulmonary vascularity on chest x-ray. A mid-diastolic rumble may also be heard.
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