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Basal Cell Nevus Syndrome – Bathing Trunk Nevus – Cowden Disease – Cylindromatosis – Dysplastic Nevus Syndrome – Epidermal Nevus – Gardner Syndrome – Hereditary Keratoacanthomas – Infantile Myofibromatosis – Multiple Endocrine Neoplasia Types 1, 2A, and 2B/3 – Multiple Leiomyomatosis – Pilomatricoma – Proteus Syndrome – Sebaceous Nevus Syndrome – Tumoral Calcinosis

Bloom Syndrome – Hartnup Disorder – Kindler Syndrome – Polymorphous Light Eruption – Rothmund-Thomson Syndrome – Xeroderma Pigmentosum

Genetic disorders are unique among diseases in that they affect families and generations, not just individuals. In the diagnosis and discussion of an inherited disorder, the recurrence risk must always be included. Will it happen again? Who is at risk to inherit? What is the magnitude of that risk? How severely will the condition be manifested? The answers to these questions depend on the mode of inheritance and the penetrance and expression of the gene(s) for the disorder.

Hay-Wells syndrome is an autosomal dominant condition characterized by ankyloblepharon filiforme adnatum, ectodermal dysplasia, and cleft palate with or without associated cleft lip (AEC syndrome). Although several reported patients had eroded skin at birth and recurrent scalp infections, these are not generally regarded as major features of the disorder. In our experience, denuded skin at birth and chronic scalp erosions complicated by infection are common features of this syndrome. Aggressive wound care in conjunction with early administration of topical or systemic antibiotics is suggested.

We report on the prenatal diagnosis of epidermolysis bullosa letalis with pyloric atresia in a pregnancy not known to be at risk for this condition. Elevated maternal serum alpha-fetoprotein levels led to ultrasonography which demonstrated gastric dilatation, consistent with pyloric atresia, and echogenic particles in the amniotic fluid, the "snowflake sign," previously described in two pregnancies of fetuses with disorders of skin sloughing. Amniotic fluid alpha-fetoprotein was markedly elevated and the acetylcholinesterase was positive. The diagnosis of epidermolysis bullosa letalis with pyloric atresia was confirmed after delivery by electron microscopy of fetal skin which showed typical changes of hypoplastic absent hemidesmosomes and separation along the dermal-epidermal junction. None of these abnormal prenatal findings are consistently present in pregnancies with epidermolysis bullosa with pyloric atresia. Thus, although useful when abnormal, when the test results are normal, the need for confirmatory fetoscopy and fetal skin biopsy remains.

Recently, two patients with the Dowling-Meara subtype of epidermolysis bullosa simplex (EBS-DM) were reported with different mutations in codon 125 of the keratin 14 gene. To determine whether these are common mutations, we screened ten EBS-DM patients and their families using single nucleotide primer extension. Four of ten unrelated EBS-DM patients had a G→-A substitution at base pair 434 of codon 125, whereas one case out of ten had a C→-T substitution at position 433 of the same codon. The G434A alteration cosegregated with the disorder in two multigenerational families; no recombination events were detected. In these two families, linkage analysis provided significant evidence in favor of linkage between G434A and the EBS-DM phenotype, with a LOD score of 3.29 at a recombination rate of 0%. Codon 125 substitutions identified in three unrelated sporadic EBS-DM patients were not found in their clinically unaffected parents. Together, these data provide compelling genetic evidence that the codon 125 substitutions are causal for EBS-DM. The high frequency of mutation at this site in individuals with EBS-DM now makes DNA-based diagnosis of this disorder feasible.

Background Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumors and hamartomas in several organs including the skin. Objective We sought to describe a new type of complex hamartoma in patients with TSC. Methods This was a retrospective clinical and histopathologic evaluation of 6 cases. Results The skin lesions consisted of large, painless, infiltrated plaques that were first noticed at birth or during early infancy on the abdomen, thigh, back, or scalp. In time, the plaques became studded with numerous follicular comedo-like openings and cysts containing and draining a keratinous or purulent material. The main histopathologic features were: abundant collagen deposition in the dermis and extending into the underlying fat; concentric, perifollicular fibrosis surrounding hair follicles; and comedones and keratin-containing cysts lined by infundibular epithelium, some of which were ruptured with secondary granulomatous reaction. Five of the 6 patients had a clinical diagnosis of TSC. Limitations Genetic testing was performed in only one patient. Conclusion This distinctive folliculocystic and collagen hamartoma has not been recognized previously in association with TSC.

Keratosis Follicularis Spinulosa Decalvans (KFSD) is a rare genetic disorder characterized by development of hyperkeratotic follicular papules on the scalp followed by progressive alopecia of the scalp, eyelashes, and eyebrows. Associated eye findings include photophobia in childhood and corneal dystrophy. Due to the genetic and clinical heterogeneity of similar disorders, a definitive diagnosis of KFSD is often challenging. Toward identification of the causative gene we reanalyzed a large Dutch KFSD family. SNP arrays (1 M) redefined the locus to a 2.9-Mb region at Xp22.12-Xp22.11. Screening of all 14 genes in the candidate region identified MBTPS2 as the candidate gene carrying a c.1523A>G (p.Asn508Ser) missense mutation. The variant was also identified in two unrelated X-linked KFSD families and cosegregated with KFSD in all families. In symptomatic female carriers, skewed X-inactivation of the normal allele matched with increased severity of symptoms. MBTPS2 is required for cleavage of sterol regulatory element-binding proteins (SREBPs). In vitro functional expression studies of the c. 1523A>G mutation showed that sterol responsiveness was reduced by half. Other missense mutations in MBTPS2 have recently been identified in patients with IFAP syndrome. We postulate that both phenotypes are in the spectrum of one genetic disorder with a partially overlapping phenotype. Hum Mutat 31:1125-1133, 2010. (C) 2010 Wiley-Liss, Inc.

Inherited epidermolysis bullosa encompasses a number of diseases, with the common finding of blister formation, after minor mechanical trauma to the skin. In some forms significant, if not eventually fatal, extracutaneous disease activity may occur. In recent years application of newer technologies has contributed substantially to an overall understanding of this collection of inherited diseases. Concurrently, many new phenotypes have been recognized, in part the result of ongoing prospective patient registries in the United States and abroad. Unfortunately, this has resulted in a massive literature that may appear to be confounded by seemingly excessive or arbitrary subdivision of epidermolysis bullosa variants. With these concerns in mind a subcommittee was established by the National Epidermolysis Bullosa Registry to summarize the current literature and to make recommendations as to the best clinical and laboratory criteria for the practical diagnosis and subclassification of patients with inherited epidermolysis bullosa.

An infant born with severe blisters on the limbs, face, trunk, and oral mucosa was diagnosed by light and electron microscopy to have recessive dystrophic epidermolysis bullosa. Transmission electron microscopy showed that the basal lamina remained with the epidermis and that the floor of the blister was exposed collagen of the papillary dermis. No banded anchoring fibrils were observed along either the roof or the floor of the blister; however, small filamentous structures, possibly immature anchoring fibrils, extended down from the lamina densa along the blister roof. Some basal and suprabasal keratinocytes contained large vesicles filled with filamentous matrix of variable electron density. Immunofluorescent staining of skin for type VII collagen showed sparse and irregular staining of type VII collagen along the blister roof, and intense intracellular labeling for type VII collagen in clusters of epidermal cells in basal and suprabasal layers. Type VII collagen appeared to be synthesized by keratinocytes but not secreted.

Skin biopsies and scale samples from nine infants and one fetus affected with harlequin ichthyosis (HI) were obtained from eight families. Epidermal differentiation was examined by morphologic and biochemical criteria and cell culture studies. Two striking abnormalities were identified; first, keratin and filaggrin expression were abnormal and varied between cases, and, second, in all cases lamellar granules were absent or abnormal, and intercellular lamellae within the stratum corneum were absent. Three HI phenotypes were distinguished by variable expression of epidermal structural proteins. Cases were classified by the absence (type 1) or presence (types 2 and 3) of keratins K6 and K16 ("hyperproliferative" keratins) and by the presence of profilaggrin in the interfollicular epidermis (types 1 and 2 only). Profilaggrin is apparently not converted to filaggrin, but it is retained in the scale. The block in profilaggrin processing may be due to an inactive phosphatase. Siblings in two families (presenting with types 1 and 2) showed the same type classification suggesting that expression of the phenotype is consistent within families but differs between families. Cultured HI keratinocytes were normal by phase microscopy, but abnormal by electron microscopy with no lamellar granules and extensive stacking of the upper layers. We conclude that harlequin ichthyosis is a genetically heterogeneous group of disorders with altered lamellar granules, intercellular lipids, and variation in expression and/or processing of structural protein markers of normal epidermal keratinization. Furthermore, the lamellar granule and structural protein defects may be indirectly related via a mechanism involving phosphorylation/dephosphorylation.

Objective.Clinical observations suggested that growth abnormalities may be present in children with ectodermal dysplasia (ED) syndromes. This study characterizes the longitudinal pattern of growth in a cohort of children with the ED syndromes. We hypothesized that (1) linear and ponderal growth abnormalities are present in children with ED from infancy through adolescence, and (2) linear and ponderal growth abnormalities differ among the clinical variants of these disorders.Methods.We studied 138 children who had ED and were registered with the National Foundation for Ectodermal Dysplasias, 74% of whom had clinical features consistent with the hypohidrotic EDs (HEDs). Height (or length) and weight measurements were obtained by standardized techniques and from review of available medical records. We converted these measurements to weight-for-height (children younger than 5 years and Results.Mean weight-for-age, weight-for-height, and BMI-for-age z scores but not height-for-age z score, were significantly lower in children with the ED syndromes than in the reference population. Mean weight-for-age and weight-for-height z scores but not BMI-for-age or height-for-age z scores increased significantly with increasing age. The mean height-for-age z score of children with the ED syndromes other than the HEDs was significantly lower than that of children with the HEDs.Conclusions.Growth abnormalities, measured as weight deficits, were present at an early age in children with the ED syndromes and persisted through adolescence. Height deficits were seen only in children with ED syndromes other than HEDs. Clinicians should evaluate carefully children with ED syndromes for growth abnormalities.

Harlequin ichthyosis (HI) is the most severe and frequently lethal form of recessive congenital ichthyosis. Although defects in lipid transport, protein phosphatase activity, and differentiation have been described, the genetic basis underlying the clinical and cellular phenotypes of HI has yet to be determined. By use of single-nucleotide–polymorphism chip technology and homozygosity mapping, a common region of homozygosity was observed in five patients with HI in the chromosomal region 2q35. Sequencing of the ABCA12 gene, which maps within the minimal region defined by homozygosity mapping, revealed disease-associated mutations, including large intragenic deletions and frameshift deletions in 11 of the 12 screened individuals with HI. Since HI epidermis displays abnormal lamellar granule formation, ABCA12 may play a critical role in the formation of lamellar granules and the discharge of lipids into the intercellular spaces, which would explain the epidermal barrier defect seen in this disorder. This finding paves the way for early prenatal diagnosis. In addition, functional studies of ABCA12 will lead to a better understanding of epidermal differentiation and barrier formation.

Although most children with Turner's syndrome are under the care of specialists, the authors of this article suggest that most affected women can best be served by their primary care practitioners, with the use of informed judgment about the need for referral to specialists. This article reviews current concepts in the genetics, diagnosis, and management of Turner's syndrome.

Connexins are integral membrane proteins forming aqueous gap junction channels that allow the diffusional exchange of ions and small metabolites between cells, thus coordinating metabolic activities in multicellular tissues. Dominant mutations in the Cx26 gene GJB2 have been shown to cause keratitis-ichthyosis-deafness (KID) syndrome, palmoplantar keratoderma associated with hearing loss, and Vohwinkel syndrome. Missense mutations in the closely related Cx30 gene GJB6 underlie Clouston syndrome (autosomal dominant hidrotic ectodermal dysplasia). We report a 6-y-old boy with phenotypic characteristics of KID syndrome as well as atrichia. In contrast to other KID syndrome patients, molecular analysis of the connexin gene GJB2 did not disclose a pathogenic mutation, although the patient was homozygous for a common polymorphism (V27I) in the coding sequence of Cx26. Nevertheless, screening of GJB6 revealed a heterozygous missense mutation (V37E) predicted to alter sequence and charge of the first transmembrane helix of Cx30, which was previously implicated in Clouston syndrome (Smith et al, 2002). The presence of a pathogenic Cx30 mutation and the lack of a pathologic molecular change in Cx26 in this patient, whose clinical features predominantly resemble KID syndrome, suggest genetic heterogeneity of KID syndrome and underscore that mutations in Cx30, similar to those in Cx26 or Cx31, can cause different phenotypes. Based on our results, connexin gene mutations should be considered in patients presenting with congenital sensorineural hearing loss and disorders of cornification, and screening of several connexin genes with known cutaneous phenotype, such as those for Cx26, Cx30, Cx30.3, and Cx31, may be required.

Purpose: To determine whether pregnancy increases the risk of renal or pulmonary complications in women with tuberous sclerosis complex (TSC). Methods: We surveyed female members of the Tuberous Sclerosis Alliance and reviewed the files of adult women seen in our genetics clinics for complications of TSC. Results: Among 145 individuals, there was no significant difference in incidence of renal and pulmonary involvement between the pregnant and never-pregnant groups, although there were differences in age at diagnosis (25 vs. 16) and current age (41 vs. 35). There was no significant difference in the rate of renal complications (57% vs. 67%, P = 0.62) or pneumothorax (40% vs. 38%, P = 1.00) for the pregnant and never-pregnant groups, respectively. Pregnancy loss in women with TSC did not differ from population risks. Conclusions: Pregnancy does not increase the risk of developing renal or pulmonary complications in women with TSC.

Erythrokeratodermia variabilis is an autosomal dominant genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The disorder maps to a cluster of connexin genes on chromosome 1p34-p35.1 and, in a subset of families, results from mutations in the gene GJB3 encoding the gap junction protein connexin-31 (Cx31). A recent report suggested the involvement of another connexin gene (GJB4) in the etiology of erythrokeratodermia variabilis. In this study, we sequenced the coding region of GJB4 in 13 unrelated erythrokeratodermia variabilis families without detectable mutations in GJB3. Mutation analysis revealed six distinct missense mutations in five families and a sporadic case of erythrokeratodermia variabilis, all of which were not found in controls. Mutation G12D, identified in an extended Dutch family, lies in the predicted amino-terminus and may interfere with the flexibility of this domain, connexin selectivity, or gating polarity of gap junction channels. Other mutations (R22H, T85P, F137L, F189Y) were located in the transmembrane domains of Cx30.3, and are predicted to hinder regulation of voltage gating or alter the kinetics of channel closure. Affected individuals of two unrelated families harbored point mutations leading to amino acid substitution F137L, which was also reported in GJB3, yet the extent and severity of hyperkeratosis was milder compared to the corresponding mutation in GJB3. Two mutations (T85P, F137L) were associated with the occurrence of rapidly changing erythematous patches with prominent, circinate, or gyrate borders in affected children but not in adults, supporting the notion that this feature is specific to Cx30.3 defects. Nevertheless, we observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. In addition to pathogenic mutations, we identified several missense mutations and a 4 bp deletion within the GJB4 coding region,, which might represent either inconsequential polymorphisms or recessive mutations. In conclusion, our results demonstrate genetic heterogeneity in erythrokeratodermia variabilis, and emphasize that intercellular communication mediated by both Cx31 and Cx30.3 is crucial for epidermal differentiation.

The goals of this study were to test the hypothesis that girls with Turner syndrome (TS) experience growth failure early in life and to establish model-based normative growth charts for 0- to 8-year-old American girls with TS. Full-term girls with TS who had 5 or more measurements of height obtained during their first 10 years of life prior to initiation of growth hormone, estrogen and/or androgen therapy were eligible for this study. A nonlinear mixed-effects model comprising the first two components of the infancy-childhood-puberty (ICP) model of growth was fitted to the longitudinal height measurements and compared with those of healthy American girls. Height measurements (n = 1,146) from 112 girls with TS (45,X: 57.1%; 45,X/46,XX: 12.5%; 46,X, iso(X): 4.5%, and other: 25.9%) were analyzed. Mean height SDS fell from –0.68 at birth to –1.60 at 1 year, –1.80 at 2 years and –1.95 at 3 years. When compared to controls (676 girls, 4,537 measurements), girls with TS grew more slowly due to three principal factors: a slow growth rate of the infancy component, a slow growth rate at the onset of the childhood component, and delayed onset of the childhood component. Traditional concepts of growth failure in TS should be revised. Physicians should consider the diagnosis of TS in any girl with unexplained failure to thrive or short stature, even in the first 3 years of life.

Background Junctional epidermolysis bullosa–pyloric atresia syndrome is recognized as a distinct autosomal recessive entity. Affected infants present with skin fragility and inability to feed due to intestinal obstruction. Despite successful surgical repair of the anatomical defect, the outcome is poor owing to poor feeding, malabsorption, failure to thrive, and sepsis. Observations In 70 cases of intestinal obstruction and epidermolysis bullosa reported in the medical literature and the 3 reported here, surgical intervention was attempted 51 times. In all except 16 infants, death occurred before age 11 months (mean age, 70 days). Renal involvement and continued failure to thrive accompanied the skin disease in survivors, who ranged in age from 30 days to 16 years (mean age, 4.0 years). Conclusions The poor prognosis of this condition must be considered when decisions are made regarding surgical correction. Attempting surgical correction may be warranted in individual circumstances, but withholding surgical intervention and providing palliative support is an acceptable alternative.

Unusual skin lesions were present at birth in four infants with Turner syndrome. The skin changes in these patients appear to have resulted either from in utero entrapment or pinching of edematous skin or from redundant skin remaining after in utero resolution of lymphedema. Distention by lymphedema is thought to cause several of the phenotypic characteristics seen in patients with Turner syndrome, including nuchal webbing and nail changes. In three of these patients the clinical appearance of the skin changes was similar to cutis verticis gyrata, marked by fixed thickened plaques in folds.

OBJECTIVE: Although hypopigmented macules are an important manifestation of tuberous sclerosis (TS), the probability of TS in healthy individuals who have hypopigmented macules is unknown. The purpose of this study was to establish the prevalence of hypopigmented macules among a cross section of the general white population. STUDY DESIGN: The skin of 423 white individuals younger than 45 years of age was screened for hypopigmented macules with ambient incandescent and fluorescent light and a Wood lamp. Indirect ophthalmoscopy was performed in patients with unexplained hypopigmentation to screen for retinal manifestations of TS. RESULTS: Twenty individuals (4.7%) had at least one hypopigmented macule. Of these, four had more than one macule. None had more than three. Two (8%) of the 25 hypopigmented macules were identified only with a Wood lamp. Indirect ophthalmoscopy was performed in 13 (65%) of these 20 individuals. None showed the retinal findings of TS. CONCLUSIONS: The prevalence of hypopigmented macules in the general population has been underestimated. The presence of a few hypopigmented macules on the skin of an otherwise healthy individual without a family history of TS need not prompt an evaluation to rule out this disorder. (J P EDIATR 1996;129:355-61)

Survey data on the sexual and social functioning of 80 adult women with Turner syndrome are described, as well as data regarding health status and self-concept. Each woman completed the Tennessee Self-Concept Scale, sections of the Derogatis Sexual Functioning Inventory, and a questionnaire covering a wide range of demographic and medical information. The women with Turner syndrome reported lower self-concept compared to a normative sample. Sexual attitudes, gender role identity, and body image were assessed. The women with Turner syndrome tended to exhibit more conservative sexual attitudes and a more negative body image. In contrast to a normative sample, the women with Turner syndrome were less likely to have been sexually active. In addition, those currently involved in a stable relationship reported a lower frequency of sexual intercourse compared to a normative sample, although they generally reported moderate to high levels of sexual satisfaction. Regression analyses revealed that health status was associated with self-concept, and that sexual satisfaction was related to both a higher frequency of intercourse and a higher self-reported health status.

Prenatal diagnosis of embryonic and fetal abnormalities is a multidisciplinary field of medicine whose techniques have been applied to an increasing number of inherited and sporadic disorders and malformations. Prenatal diagnosis for epidermolysis bullosa (EB) by fetoscopy was first reported in 1980.1 Since that initial report, numerous successful diagnoses and exclusions of EB in pregnancies at risk have been published.

An interesting feature of neurofibromatosis type 1 (NF1) is its high mutation rate of 1 x 10(-4) per gamete per generation. The molecular basis for frequent NF1 mutation in unknown; the gene is not deletion prone. We have found that in all ten families examined, the apparent new NF1 mutation occurred on the paternally-derived chromosome. The probability of observing this result by chance is less than 0.001 assuming an equal frequency of mutation of paternal and maternal NF1 genes. We hypothesize a role for genomic imprinting that may either enhance mutation of the paternal NF1 gene or confer protection from mutation to the maternal NF1 gene.

This report presents a family with two individuals in two successive generations who were affected by annular pancreas and high duodenal obstruction. An argument for autosomal dominant transmission and implications for appropriate team management are discussed.

Thirteen patients with hypopigmentation of the skin characteristic of hypomelanosis of Ito, and with developmental disabilities or structural malformations, or both, were examined at our center. Eight were found to have abnormal karyotypes in lymphocytes, fibroblasts, or both. No single clinical feature was predictive of chromosome imbalance in this group of patients. Cytogenetic findings included a balanced de novo X-autosome translocation; ring 10; 45,X/46,X,+ring; mosaic del 13q11 (fibroblasts); mosaic triploidy (fibroblasts); mosaic tetrasomy 12p (fibroblasts); mosaic apparently balanced 15;22 translocation (peripheral blood); and mosaic trisomy 18 (peripheral blood). Hypomelanosis of Ito is characterized by swirly hypopigmentation or depigmentation of the skin with or without other malformations. Autosomal dominant, autosomal recessive, and X-linked dominant inheritance have been suggested but not confirmed. Chromosomal aneuploidy has also been reported. We believe that hypomelanosis of Ito is an etiologically heterogeneous physical finding, and recommend karyotyping of multiple tissues of all patients with abnormal cutaneous pigmentation associated with developmental delay or structural malformations.

Background. Turner syndrome (gonadal dysgenesis with sex chromosome abnormalities) is recognized to be a disorder in which cardiovascular malformations are common. The prevalence and natural history of these findings, the risk for aortic dissection, and the occurrence of cardiovascular disease have all been the subject of debate, as have been the American Academy of Pediatrics recommendations for cardiac screening of patients with Turner syndrome.Objective. To evaluate a large population of patients both cross-sectionally and longitudinally to determine the prevalence of cardiovascular malformations, the risk for dissection of the aorta, to determine whether there are phenotype:karyotype correlations that can allow for specific recommendations, and to devise an appropriate screening protocol.Design and Methods. Data have been collected for patients with Turner syndrome. These individuals have been seen in an ongoing clinic established for the study of the natural history of Turner syndrome. Data from physical examinations, evaluations by cardiologists, echocardiography results, medical and surgical complications, medical records, and causes of death were analyzed. A total of 244 of 462 individuals in this population with karyotype-proven Turner syndrome could be evaluated because echocardiograms had been obtained. In addition, the medical literature was reviewed for occurrences of aortic dissection in patients with Turner syndrome.Results. A total of 136 (56%) of 244 of these patients had cardiovascular abnormalities, 96 (71%) were structural, 40 (29%) were functional, including hypertension (HBP), mitral valve prolapse and conduction defects. Coarctation of the aorta and bicuspid aortic valve, alone or in combination, comprised >50% of the cardiac malformations. Bicuspid valve was often not detected by examination, but only by echocardiography. Aortic dissection occurred in three of the patients. In one, it was traumatic; in a second, it occurred at the site of coarctation repair. The third patient had long-standing HBP with malignant obesity. In the literature, there have been 42 case reports of aortic dissection in Turner syndrome. In all except 5, predisposing risk factors of coarctation, bicuspid aortic valve, and/or HBP were present. Of these 5, sufficient information regarding predisposing risk factors was provided for only 2. No phenotype:karyotype correlations could be drawn with any certainty.Conclusions. When the diagnosis of Turner syndrome is made, a screening echocardiogram should be obtained. Referral to a cardiologist first may be appropriate, but physical examination does not substitute for visualization. Individuals with and without evidence of structural cardiac malformations should be monitored for HBP on a lifelong basis. In the absence of structural cardiac malformations or HBP, the risk for aortic dissection appears small, and repeated echocardiography or magnetic resonance imaging to follow aortic root diameters does not appear to be warranted based on data currently available. Protocols for following patients with structural malformations need to be individualized, and wholesale recommendations have little merit. A longitudinal study using magnetic resonance imaging or cardiac echocardiography to establish normal parameters for aortic root diameters and to follow aortic root changes is needed.

I read with great interest the article by Luther and colleagues in a recent issue of theArchives 1 reviewing their herculean analysis of the development of melanocytic nevi over time in children. However, the authors presented no information regarding patients' family histories of melanocytic nevi. Although Luther et al looked at predisposing risk factors that may be genetic in origin, eg, hair color and skin color, they did not appear to evaluate what is probably the single most important factor in regard to the development of nevi: the presence of nevi in a parent. My second concern is whether there is any correlation between the number of nevi at the first visit and the number developed over time. In other words, do children who have greater numbers of nevi in early childhood have a higher risk to develop even proportionately greater numbers over time, or is sun exposure itself

Epidermolysis bullosa simplex—Dowling-Meara (EBS-DM) is a severe form of EBS, with oral and nail involvement as well as severe skin blistering. Reports1,2of treatment with 5-hydroxytryptamine—2 antagonists reducing the severity of blisters in subjects with EBS-DM prompted us to study cyproheptadine hydrochloride therapy in 13 individuals with a diagnosis of EBS-DM confirmed by electron microscopic examination. Participants served as their own controls. There was a 2-week observational period, an initial 6-week period during which cyproheptadine was taken daily, a 4-week period with no treatment, and a second 6-week regimen of daily administration of cyproheptadine. Standard dosages of cyproheptadine were used.3The study was designed in this manner in an attempt to compensate for temporal variation in blister formation as well as variations in season, weather, and activity levels of the participants. Subjects were asked to record the number of blisters lanced each day rather than the

Advances in technology have resulted in an explosion of information about the molecular bases of human inheritance and human disease. Much of the new terminology is daunting, and it is becoming increasingly difficult to remain current. This article briefly reviews some of the changes in our understanding of the rules of inheritance and recurrence risks for genetic disorders. Further readings are suggested, and a glossary of technical terms is provided. ( Arch Dermatol. 1993;129:1409-1416) You and I grew up in simpler times when the laws of Mendel the geneticist were immutable and pure. (As Melodie Williams and F. Clarke Fraser pointed out in their article on Clouston ectodermal dysplasia [ Can Med Assoc J. 1967;96:36-38], the laws of Mendel the monk are frequently transgressed.) Peas were round or wrinkled, eyes were blue or brown, and your parents' blood groups were, hopefully, compatible with yours. Once we had mastered the concepts of autosomal