Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.

Homozygous variants in MAPRE2 and CDON in individual with skin folds, growth delay, retinal coloboma, and pyloric stenosis.

Cases with multiple molecular diagnoses are challenging to diagnose clinically, yet may be resolved by unbiased exome sequencing analysis. We report an infant with developmental delay, severe growth delay, dysmorphic features, and multiple congenital anomalies including retinal coloboma, congenital pyloric stenosis, and circumferential skin creases. Exome sequencing identified a homozygous missense variant in MAPRE2 and a homozygous stopgain (nonsense) variant in CDON. Variants in MAPRE2, encoding a regulator of microtubule dynamics, lead to congenital symmetric circumferential skin creases type 2, with associated dysmorphism, small growth parameters, and congenital cardiac and genital anomalies. Monoallelic variants in CDON, encoding a coreceptor for sonic hedgehog, have been associated with autosomal dominant pituitary stalk interruption syndrome and holoprosencephaly. Cdon-/- mice have multiple eye defects including coloboma, consistent with the observed human phenotype. Thus, the complex phenotypic presentation of the infant may potentially be attributed to a dual molecular diagnosis. Furthermore, we present CDON as a candidate gene for coloboma formation in addition to the known holoprosencephaly phenotype, and propose to expand the allelic spectrum of CDON to variants associated with autosomal recessive inheritance in addition to dominant inheritance.

Integrin beta 4 mutations associated with junctional epidermolysis bullosa with pyloric atresia.

Pyloric atresia associated with junctional epidermolysis bullosa (PA-JEB), is a rare inherited disorder characterized by pyloric stenosis and blistering of the skin as primary manifestations. We demonstrate that in one PA-JEB patient the disease resulted from two distinct mutations in the beta 4 integrin gene alleles. The paternal mutation consists of a one base pair deletion causing a shift in the open reading frame, and a downstream premature termination codon. The maternal mutation occurs in a donor splice site, and results in in-frame exon skipping involving the cytoplasmic domain of the polypeptide. Our results implicate mutations in the beta 4 integrin gene in some forms of PA-JEB.

Familial aggregation and heritability of pyloric stenosis.

CONTEXT: Pyloric stenosis is the most common condition requiring surgery in the first months of life. Case reports have suggested familial aggregation, but to what extent this is caused by common environment or inheritance is unknown. OBJECTIVES: To investigate familial aggregation of pyloric stenosis from monozygotic twins to fourth-generation relatives according to sex and maternal and paternal contributions and to estimate disease heritability. DESIGN, SETTING, AND PATIENTS: Population-based cohort study of 1,999,738 children born in Denmark between 1977 and 2008 and followed up for the first year of life, during which 3362 children had surgery for pyloric stenosis. MAIN OUTCOME MEASURE: Familial aggregation of pyloric stenosis, evaluated by rate ratios. RESULTS: The incidence rate (per 1000 person-years) of pyloric stenosis in the first year of life was 1.8 for singletons and 3.1 for twins. The rate ratios of pyloric stenosis were 182 (95% confidence interval [CI], 70.7-467) for monozygotic twins, 29.4 (95% CI, 9.45-91.5) for dizygotic twins, 18.5 (95% CI, 13.7-25.1) for siblings, 4.99 (95% CI, 2.59-9.65) for half-siblings, 3.06 (95% CI, 2.10-4.44) for cousins, and 1.60 (95% CI, 0.51-4.99) for half-cousins. We found no difference in rate ratios for maternal and paternal relatives of children with pyloric stenosis and no difference according to sex of cohort member or sex of relative. The heritability of pyloric stenosis was 87%. CONCLUSION: Pyloric stenosis in Danish children shows strong familial aggregation and heritability.

Congenital generalized lipodystrophy: The evaluation of clinical follow-up findings in a series of five patients with type 1 and two patients with type 4.

Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by lipoatrophy affecting the face, limbs and trunk, acromegaloid features, hepatomegaly, hypertriglyceridemia, and insulin resistance. The aim of this study is to evaluate the long-term follow-up findings including gastrointestinal and cardiac manifestations of the patients with CGL1 and CGL4, caused by mutations in the AGPAT2 and CAVIN1 genes, respectively. Two patients aged 2 and 9 years with the same biallelic CAVIN1 mutation and five patients aged between 6 months and 11 years 4 months with AGPAT2 mutations have been followed up for 3-9 years. The patients were between 7 and 20 years of age at their last examination. One of the two patients with CGL4 had congenital pyloric stenosis. The other patient with CGL4 have developed recurrent duodenal perforations which have not been reported in CGL patients previously. The pathological examination of duodenal specimens revealed increased subserosal fibrous tissue and absent submucosal adipose tissue. None of the five CGL1 patients had gastrointestinal problems. Two patients with CGL4 developed hypertrophic cardiomyopathy (HCMP) and severe cardiac arrhythmia, only one patient with CGL1 had HCMP. Hyperinsulinemia was detected in one patient with CGL4 and three patients with CGL1, these three CGL1 patients also had acanthosis nigricans. Hepatic steatosis was detected in one patient with CGL4 and two patients with CGL1 by ultrasonography. In conclusion, these findings suggest that CGL4 patients should also be carefully followed up for gastrointestinal and cardiac manifestations.

Molecular cytogenetic characterisation of partial trisomy 9q in a case with pyloric stenosis and a review.

Partial trisomy 9q represents a rare and heterogeneous group of chromosomal aberrations characterised by various clinical features including pyloric stenosis. Here, we describe the case of a 1 year old female patient with different dysmorphic features including pyloric stenosis and prenatally detected partial trisomy 9q. This partial trisomy 9q has been analysed in detail to determine the size of the duplication and to characterise the chromosomal breakpoints. According to the data gained by different molecular cytogenetic techniques, such as fluorescence in situ hybridisation (FISH) with whole and partial chromosome painting probes, yeast artificial chromosome (YAC) probes, and comparative genomic hybridisation (CGH), the derivative chromosome 9 can be described as dup(9)(pter-->q22. 1::q31.1-->q22.1::q31.1--> q22.1::q31.1-->qter). Four breakpoint spanning YACs have been identified (y806f02, y906g6, y945f5, and y747b3) for the proximal breakpoint. According to this new case and previously published data, the recently postulated putative critical region for pyloric stenosis can be narrowed down to the subbands 9q22.1-q31.1 and is the result of either partial trisomy of gene(s) located in this region or a gene disrupted in 9q31.

A goodness-of-fit test for the polygenic threshold model: application to pyloric stenosis.

A new test of goodness of fit for the polygenic threshold model is proposed. This test, when applied to disorders showing different incidence rates in males and females, is designed to account for ascertainment in more detail than previously done by other investigators. This is accomplished by computing the expected distribution of nuclear families with more than one affected sib conditioned on several family-dependent variables, including whether each family was ascertained via only affected boys or via at least one affected girl. A direct measure of the probability of observing a data set is thereby derived. The test, when applied to data on pyloric stenosis, exposes the critical nature of the ascertainment procedures. Different levels of statistical significance are obtained when mode of ascertainment is taken into account than when the mode of ascertainment is ignored.

Duplication of part of 9q due to maternal 12;9 inverted insertion associated with pyloric stenosis.

We report on a 9-month-old boy who had duplication of the long arm of chromosome 9 [46,XY, -12, +der(12) inv ins (12;9)(p13;q32q13)mat.]. The clinical manifestations of the patient were different from those seen in distal 9q duplication. Pyloric stenosis appears to be common in cases with proximal 9q duplications.

Early death in two sisters with Hennekam syndrome.

We report on two sisters with facial anomalies, protein-losing enteropathy, and intestinal lymphangiectasia consistent with the diagnosis of Hennekam syndrome. Both patients had a number of other anomalies not previously described in this autosomal recessive disorder, i.e., primary hypothyroidism, hypertrophic pyloric stenosis, and an early fatal outcome. These cases support the autosomal recessive transmission and the expansion of the phenotype of the Hennekam syndrome.

Pyloric stenosis--a report of triplet females and notes on its inheritance.

Pyloric stenosis has been reported in multiple sibs and multiple births, A case of the disease affecting triplets is reported, the second in the literature. The expression of pyloric stenosis is dependent upon the genetic influence of ancestors affected with the disease, as well as unknown environmental influences in the postnatal period. Descendants of affected females are the most likely to develop pyloric stenosis.

Congenital gastric outlet obstruction.

Two additional cases of congenital gastric outlet obstruction are presented. A comprehensive review of the literature was undertaken and as a result a classification for congenital gastric outlet obstruction is suggested. The management of the cases reported in the literature has also been reviewed together with the genetics of pyloric atresia and associated dermatologic lesions. Guidelines are given for the management of congenital gastric outlet obstruction with and without associated, inherited dermatologic conditions.

Achalasia and other diseases associated with disorders of gastrointestinal motility.

The aetiology of achalasia is unknown, but it has been suggested that it is congenital in origin and associated with such disorders as infantile pyloric stenosis or Hirschsprung's disease. Another reported association has been with Hodgkin's disease. A survey of 126 patients with achalasia, and their first degree relatives was undertaken to record the prevalence of infantile pyloric stenosis, Hirschsprung's disease and Hodgkin's disease. The prevalence of motor neurone disease and diabetes, which can be associated with motility disorders of the oesophagus, were also recorded as a measure of the efficiency of the questionnaire. None of the 126 patients with achalasia suffered from pyloric stenosis, Hirschsprung's disease, Hodgkin's lymphoma or motor neurone disease. There was no increased frequency of these disorders amongst first degree relatives. There appears to be no common aetiology for aganglionic bowel disease, and no obvious association between Hodgkin's disease and achalasia. Diabetes is seen with the expected frequency amongst patients with achalasia and their relatives, indicating the adequacy of the questionnaire.

Isolated hypertrophic pyloric stenosis and perinatal factors.

Infantile hypertrophic pyloric stenosis (IHPS) is a common condition requiring surgical intervention during the first weeks of life. Up to now the exact etiology of IHPS remains unclear and it is probable that several predisposing risk factors would be associated with the condition. Prompted by the observation that some perinatal factors may be involved in IHPS etiology, we evaluated 171 isolated cases referred to the Sicilian Registry of Congenital Anomalies. Our results show that some perinatal factors like sex ratio imbalance and parity are associated with IHPS, but further investigation is needed to clarify the relationship between genes and other factors involved in IHPS etiology. Therefore the presence of these perinatal factors may be accurately evaluated in genetic counseling to provide a perspective of recurrence prevention.

Familial congenital short small bowel with associated defects. A long-term survival.

In 1974, Royer et al. described a familial syndrome consisting of a short and sluggish small bowel, malrotation of the gut, and pyloric stenosis. These authors stressed the uniformly fatal outcome of their four cases, as well as other possibly unrecognized cases previously described in the literature. The present report deals with two more familial cases, of which one represents a long-term survivor of the syndrome. The intensive work of maintaining nutrition, controlling infection, and managing the complications of associated defects are described.

[Familial malformation recurrence in congenital heart disease]. / Recurrencia malformativa familiar en las cardiopatías congénitas.

The intensity and degree of familial association in a series of congenital heart diseases has provided 204 cases of familial malformation recurrence. There was total concordance for 27% of first degree relatives, 18.5% of those of second degree, and 9% of third degree; partial concordance was present in 15, 18 and 41%; system concordance in 27, 44, and 43%; total discordance in 31, 18.5, and 5%. Anencephaly, hydrocephaly, cleft lip-palate, pyloric stenosis, and cryptorchidism were repeatedly present with a highly significant incidence.

Infantile hypertrophic pyloric stenosis: a Dunedin review.

Patients who had undergone a Ramstedt pyloromyotomy for infantile hypertrophic pyloric stenosis in Dunedin over a 10 year period to June 1984 were reviewed. Forty-two cases were recorded. More congenital anomalies than expected, a declining rate of wound complications and a high rate of a positive family history were found. The history is reviewed, the data presented and the results discussed.

[Hypertrophic stenosis of the pyloric canal: genetic and familial incidence]. / Stenosi ipertrofica del canale pilorico: incidenza genetica e familiare.

The Authors hereby review the literature concerning hypertrophic pyloric stenosis, with particular reference to the genetic and familial influence. They present their cases of 49 children; out of these 3 pairs of biovular twins out of which only one of the twin babies was affected and 2 similar twins both of which were affected. In conclusion they are confirming the importance of a genetic component, influenced by environmental factors, on the origin of hypertrophic pyloric stenosis.

[Hypertrophic stenosis of the pylorus. Correlations with allergy to milk proteins and atopy]. / Stenosi ipertrofica del piloro. Correlazioni con l'allergia alle proteine del latte e con l'atopia.

We performed a study concerning the relationship between hypertrophic pyloric stenosis (HPS), atopy and cow's milk protein allergy (CMPA). Familial history of atopy was documented in 17 (44.7%) of 38 infants having undergone Ramstedt pyloromyotomy for HPS, in 12 (23%) of 52 infants having undergone surgery for inguinal hernia and in 53 (26.9%) of 290 normal controls (significant differences between HPS and other groups). Moreover 9 (23.6%) of 38 infants with HPS presented personal history of eczema at follow-up compared with 3 (5.7%) infants having undergone surgery for inguinal hernia (p less than 0.01). A significant difference between HPS and other groups was also found when looking for familial history of CMPA: 26.3% vs % and 2.5% respectively (p less than 0.001). Eventually we discovered a higher than expected incidence of CMPA both in a retrospectively evaluated group of HPS and in 24 infants undergone Ramstedt pyloromyotomy and followed according to a standardized protocol for a mean period of 4 months (16.6%). The etiology of HPS remains obscure. Our data however suggest some relationship between HPS, atopy and particularly CMPA.

[Hypertrophic pyloric stenosis in twins]. / Wrodzone przerostowe zwezenie odzwiernika u blizniat.

Two cases of the pyloric stenosis in twins were described. Etiology of the illness stays still difficult to explain. It is generally accepted that pyloric stenosis has multifactorial inheritance. Familial occurrence of the illness in twins suggests this etiology.