Hypercalciuria and nephrolithiasis: Expanding the renal phenotype of Donnai-Barrow syndrome.

Whole exome sequencing detected novel likely pathogenic variants in LRP2 gene in 2 patients presenting with hearing and vision loss, and the Dent disease (DD) classical renal phenotype, that is, low molecular weight proteinuria (LMWP), hypercalciuria and nephrocalcinosis/nephrolithiasis. We propose that a subset of patients presenting as DD may represent unrecognized cases or mild forms of Donnai-Barrow/facio-oculo-acustico-renal (DB/FOAR) syndrome or be on the phenotypic continuum between the 2 conditions.

Description of common musculoskeletal findings in Williams Syndrome and implications for therapies.

Williams syndrome (WS), also referred to as Williams-Beuren syndrome (WBS), is a relatively rare genetic disorder affecting ∼1/10,000 persons. Since the disorder is caused by a micro-deletion of ∼1.5 Mb, it is not surprising that the manifestations of WS are extremely broad, involving most body systems. In this paper, we primarily focus on the musculoskeletal aspects of WS as these findings have not been the subject of a comprehensive review. We review the MSK features commonly seen in individuals with WS, along with related sensory and neurological issues interacting with and compounding underlying MSK abnormalities. We end by providing perspective, particularly from the vantage point of a physical therapist, on therapeutic interventions to address the most common MSK and related features seen in WS. Clin. Anat. 29:578-589, 2016. © 2016 Wiley Periodicals, Inc.

Prevalence and penetrance of ZFPM2 mutations and deletions causing congenital diaphragmatic hernia.

Zinc finger protein, FOG2 family member 2 (ZFPM2) (previously named FOG2) gene defects result in the highly morbid congenital diaphragmatic hernia (CDH) in humans and animal models. In a cohort of 275 CDH patient exomes, we estimated the prevalence of damaging ZFPM2 mutations to be almost 5%. Genetic analysis of a multigenerational family identified a heritable intragenic ZFPM2 deletion with an estimated penetrance of 37.5%, which has important implications for genetic counseling. Similarly, a low penetrance ZFPM2 frameshift mutation was observed in a second multiplex family. Isolated CDH was the predominant phenotype observed in our ZFPM2 mutation patients. Findings from the patients described herein indicate that ZFPM2 point mutations or deletions are a recurring cause of CDH.

High prevalence of diabetes and pre-diabetes in adults with Williams syndrome.

A standard oral glucose tolerance test (OGTT) was administered to 28 adults with Williams syndrome (WS). Three quarters of the WS subjects showed abnormal glucose curves, meeting diagnostic criteria for either diabetes or the pre-diabetic state of impaired glucose tolerance. Fasting mean glucose and median insulin levels did not differ significantly in the total WS cohort versus age-gender-BMI matched controls, though the glucose area under the curve was greater in the WS subjects. HbA1c levels were not as reliable as the OGTT in diagnosing the presence of diabetes. Given the high prevalence of impaired glucose regulation, adults with WS should be screened for diabetes, and when present should be treated in accordance with standard medical practice. Hemizygosity for a gene mapping to the Williams syndrome chromosome region (WSCR) is likely the major factor responsible for the high frequency of diabetes in WS. Syntaxin-1A is a prime candidate gene based on its location in the WSCR, its role in insulin release, and the presence of abnormal glucose metabolism in mouse models with aberrantly expressed Stx-1a.

Genetic aspects of human congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a common major malformation affecting 1/3000-1/4000 births, which continues to be associated with significant perinatal mortality. Much current research is focused on elucidating the genetics and pathophysiology contributing to CDH to develop more effective therapies. The latest data suggest that many cases of CDH are genetically determined and also indicate that CDH is etiologically heterogeneous. The present review will provide a brief summary of diaphragm development and model organism work most relevant to human CDH and will primarily describe important human phenotypes associated with CDH and also provide recommendations for diagnostic evaluation of a fetus or infant with CDH.

Findings from aCGH in patients with congenital diaphragmatic hernia (CDH): a possible locus for Fryns syndrome.

Congenital diaphragmatic hernia (CDH) is a common and often devastating birth defect that can occur in isolation or as part of a malformation complex. Considerable progress is being made in the identification of genetic causes of CDH. We applied array-based comparative genomic hybridization (aCGH) of approximately 1Mb resolution to 29 CDH patients with prior normal karyotypes who had been recruited into our multi-site study. One patient, clinically diagnosed with Fryns syndrome, demonstrated a de novo 5Mb deletion at chromosome region 1q41-q42.12 that was confirmed by FISH. Given prior reports of CDH in association with cytogenetic abnormalities in this region, we propose that this represents a locus for Fryns syndrome, a Fryns syndrome phenocopy, or CDH.

Pulmonary hypoplasia and persistent pulmonary hypertension in the newborn with homozygous alpha-thalassemia: a case report and review of the literature.

The survival of infants with homozygous alpha-thalassemia, once considered a lethal diagnosis, is now possible through in utero and postnatal diagnostic and therapeutic interventions. We report the survival of a newborn with homozygous alpha-thalassemia complicated by pulmonary hypoplasia and persistent pulmonary hypertension, an association not previously reported.

Differences by sex in cardiovascular disease in Williams syndrome.

OBJECTIVE: To analyze the incidence and severity of cardiovascular disease in patients with Williams syndrome (WS) and to identify factors contributing to its variable expression. METHODS: Clinical data on patients with WS were collected from several WS centers. Elastin gene deletions were confirmed in all patients. Age at diagnosis, growth data, and cardiovascular diagnoses were recorded retrospectively. Cardiac diagnoses were made on the basis of echocardiographic data. The severity of supravalvular aortic stenosis was recorded by using a 4-step scale (none, mild, moderate, severe). RESULTS: Statistical analysis of the data revealed that the severity of both supravalvular aortic stenosis and total cardiovascular disease was significantly greater in male patients than female patients (P <.002 and P <.002, respectively; Kruskal-Wallis rank-sum test). This difference was not accounted for by differences in height, weight, body mass index, or head circumference. The clinical diagnosis of WS was made at a significantly younger age in male patients (P <.01, Student t test). Earlier diagnosis was partly because of increased incidence and severity of cardiovascular disease. Another determinant of early diagnosis was low body mass index. CONCLUSION: Penetrance and severity of the elastin arteriopathy in patients with WS is affected by sex. We hypothesize that differences by sex in arterial stenoses may be related to prenatal hormonal effects. Future epidemiologic and in vitro studies may provide additional insight into the pathogenetic mechanisms of these observed differences.

A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome.

Williams-Beuren syndrome (WBS) is most often caused by hemizygous deletion of a 1.5-Mb interval encompassing at least 17 genes at 7q11.23 (refs. 1,2). As with many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region. Here, we report the use of interphase fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS region. We have observed that the inversion is hemizygous in 3 of 11 (27%) atypical affected individuals who show a subset of the WBS phenotypic spectrum but do not carry the typical WBS microdeletion. Two of these individuals also have a parent who carries the inversion. In addition, in 4 of 12 (33%) families with a proband carrying the WBS deletion, we observed the inversion exclusively in the parent transmitting the disease-related chromosome. These results suggest the presence of a newly identified genomic variant within the population that may be associated with the disease. It may result in predisposition to primarily WBS-causing microdeletions, but may also cause translocations and inversions.

Novel and recurrent mutations in lamin A/C in patients with Emery-Dreifuss muscular dystrophy.

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by slowly progressive muscle wasting and weakness; early contractures of the elbows, Achilles tendons, and spine; and cardiomyopathy associated with cardiac conduction defects. Clinically indistinguishable X-linked and autosomal forms of EDMD have been described. Mutations in the STA gene, encoding the nuclear envelope protein emerin, are responsible for X-linked EDMD, while mutations in the LMNA gene encoding lamins A and C by alternative splicing have been found in patients with autosomal dominant, autosomal recessive, and sporadic forms of EDMD. We report mutations in LMNA found in four familial and seven sporadic cases of EDMD, including seven novel mutations. Nine missense mutations and two small in-frame deletions were detected distributed throughout the gene. Most mutations (7/11) were detected within the LMNA exons encoding the central rod domain common to both lamins A/C. All of these missense mutations alter residues in the lamin A/C proteins conserved throughout evolution, implying an essential structural and/or functional role of these residues. One severely affected patient possesed two mutations, one specific to lamin A that may modify the phenotype of this patient. Mutations in LMNA were frequently identified among patients with sporadic and familial forms of EDMD. Further studies are needed to identify the factors modifying disease phenotype among patients harboring mutations within lamin A/C and to determine the effect of various mutations on lamin A/C structure and function.

Truncating mutations in FOXC2 cause multiple lymphedema syndromes.

Hereditary lymphedemas are developmental disorders of the lymphatics resulting in edema of the extremities due to altered lymphatic flow. One such disorder, the lymphedema-distichiasis syndrome, has been reported to be caused by mutations in the forkhead transcription factor, FOXC2. We sequenced the FOXC2 gene in 86 lymphedema families to identify mutations. Eleven families were identified with mutations predicted to disrupt the DNA binding domain and/or C-terminal alpha-helices essential for transcription activation by FOXC2. Broad phenotypic heterogeneity was observed within these families. The phenotypes observed overlapped four phenotypically defined lymphedema syndromes. FOXC2 appears to be the primary cause of lymphedema-distichiasis syndrome and is also a cause of lymphedema in families displaying phenotypes attributed to other lymphedema syndromes. Our data demonstrates that the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.

46,XX gonadal dysgenesis, short stature, and recurrent metabolic acidosis in two sisters.

Gonadal (ovarian) dysgenesis in 46,XX individuals is genetically heterogeneous. We report on two sisters who, in addition to primary ovarian failure, have marked short stature and recurrent episodes of dehydration with metabolic acidosis. Studies performed during one of these episodes suggested mitochondrial dysfunction; however, results of biochemical analysis of electron transport chain activity in skeletal muscle and mitochondrial DNA studies were normal. We discuss the phenotype in relation to previously described conditions of 46,XX gonadal dysgenesis. We suggest this constellation of findings represents a new syndrome.

KCNE1-like gene is deleted in AMME contiguous gene syndrome: identification and characterization of the human and mouse homologs.

We describe the identification and characterization of a new gene deleted in the AMME contiguous gene syndrome. This gene is predominantly expressed in heart, skeletal muscle, spinal cord, and brain. Screening of placenta and NT2 cDNA libraries enabled us to obtain the 1.5-kb full-length transcript, which shows a 426-bp open reading frame. Since the resulting 142-amino-acid peptide has a single putative transmembrane domain and a weak but suggestive homology with KCNE1 (minK), a protein associated with the KCNQ1 potassium channel (KVLQT1), we named this new gene KCNE1-like (KCNE1L). To obtain greater insight into this new member of an apparently distinct protein family, we have identified and characterized the homologous mouse gene (Kcne1l), which encodes a peptide of 143 amino acids with 91% homology and 80% identity. The expression pattern of mouse Kcne1l in the developing embryo revealed strong signal in ganglia, in the migrating neural crest cells of cranial nerves, in the somites, and in the myoepicardial layer of the heart. The specific distribution in adult tissues, the putative channel function, and the expression pp6tern in the developing mouse embryo suggest that KCNE1L could be involved in the development of the cardiac abnormalities as well as of some neurological signs observed in patients with AMME contiguous gene syndrome.

PTEN mutation spectrum and genotype-phenotype correlations in Bannayan-Riley-Ruvalcaba syndrome suggest a single entity with Cowden syndrome.

Germline mutations in the tumour suppressor gene PTEN have been implicated in two hamartoma syndromes that exhibit some clinical overlap, Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRR). PTEN maps to 10q23 and encodes a dual specificity phosphatase, a substrate of which is phosphatidylinositol 3,4,5-triphosphate, a phospholipid in the phosphatidylinositol 3-kinase pathway. CS is characterized by multiple hamartomas and an increased risk of benign and malignant disease of the breast, thyroid and central nervous system, whilst the presence of cancer has not been formally documented in BRR. The partial clinical overlap in these two syndromes is exemplified by the hallmark features of BRR: macrocephaly and multiple lipomas, the latter of which occur in a minority of individuals with CS. Additional features observed in BRR, which may also occur in a minority of CS patients, include Hashimoto's thyroiditis, vascular malformations and mental retardation. Pigmented macules of the glans penis, delayed motor development and neonatal or infant onset are noted only in BRR. In this study, constitutive DNA samples from 43 BRR individuals comprising 16 sporadic and 27 familial cases, 11 of which were families with both CS and BRR, were screened for PTEN mutations. Mutations were identified in 26 of 43 (60%) BRR cases. Genotype-phenotype analyses within the BRR group suggested a number of correlations, including the association of PTEN mutation and cancer or breast fibroadenoma in any given CS, BRR or BRR/CS overlap family ( P = 0.014), and, in particular, truncating mutations were associated with the presence of cancer and breast fibroadenoma in a given family ( P = 0.024). Additionally, the presence of lipomas was correlated with the presence of PTEN mutation in BRR patients ( P = 0.028). In contrast to a prior report, no significant difference in mutation status was found in familial versus sporadic cases of BRR ( P = 0.113). Comparisons between BRR and a previously studied group of 37 CS families suggested an increased likelihood of identifying a germline PTEN mutation in families with either CS alone or both CS and BRR when compared with BRR alone ( P = 0.002). Among CS, BRR and BRR/CS overlap families that are PTEN mutation positive, the mutation spectra appear similar. Thus, PTEN mutation-positive CS and BRR may be different presentations of a single syndrome and, hence, both should receive equal attention with respect to cancer surveillance.

Early puberty in Williams syndrome.

Pubertal development was evaluated in nine males and 16 females with Williams syndrome (WS). Our results indicate that puberty in WS occurred earlier than in published population controls; specifically, 90% of menstruating females reached menarche and 83% of pubertal males showed Tanner III pubic hair development prior to the age of 12 years. The sequence of pubertal development was normal, bone age was always consistent with, or in excess of, chronological age, and there was evidence of central (hypothalamic-pituitary mediated) activation as the cause of early puberty in a subset of subjects.

Elevated ambulatory blood pressure in 20 subjects with Williams syndrome.

Previous studies report conflicting frequencies of hypertension in cohorts of patients with Williams syndrome (WS). We studied blood pressure (BP) in WS using 24-hour ambulatory BP monitoring. This technique reliably measures day- and nighttime BP in a subject's natural environment and provides better prognostic information on long-term risks of hypertension than casual BP determinations. Twenty WS subjects evaluated through a multidisciplinary WS clinic and 35 age and gender-matched controls were studied. We found that WS subjects had significantly higher ambulatory BP than controls. After controlling for age, sex, and weight, the diagnosis of WS added approximately 10 mmHg to mean daytime and nighttime BPs. Hypertension, as defined by elevated mean daytime BP, was present in 40% of WS subjects versus 14% of controls (P < 0.05); among the children studied this difference was even more dramatic with 46% of WS children versus 6% of control children classified as hypertensive (P = 0.01). We also demonstrated normal diurnal BP variation but no evidence of a "white coat" effect or increased BP variability. Interestingly, parental reporting of a history of infantile hypercalcemia was strongly associated with the presence of hypertension (P = 0.008). Our data demonstrate that both children and adults with WS have higher mean BP and higher frequency of hypertension than healthy controls. Thus, elevated BP readings in the office setting should not be dismissed but require more thorough assessment.

Identification and characterization of a highly conserved protein absent in the Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E) contiguous gene deletion syndrome (AMME).

We recently described a novel contiguous gene deletion syndrome (AMME) in Xq22.3 that includes Alport syndrome (A), mental retardation (M), midface hypoplasia (M), and elliptocytosis (E). While the Alport syndrome is due to deletion of the COL4A5 gene, no other genes are known in the region with the exception of our recent finding of the FACL4 gene. In our effort to isolate additional genes from the deleted region, we have identified the gene named AMMECR1 (Alport syndrome, mental retardation, midface hypoplasia, and elliptocytosis chromosomal region gene 1). RACE experiments and screening of cDNA libraries enabled us to obtain the entire ORF of the gene (1002 bp) followed by about 2 kb of 3'UTR. AMMECR1 is composed of six exons, shows a ubiquitous 6.5-kb transcript, and codes for a protein with a molecular mass of 35.5 kDa. Sequence analysis revealed that this gene is conserved in several species ranging from Caenorhabditis elegans and yeast to micro-organisms. Exon 2 of AMMECR1 encodes a domain consisting of six amino acids identically conserved throughout the course of evolution and whose function is as yet unknown. Analysis of the predicted protein product using ExPAsy tools raises the possibility that the gene may code for a regulatory factor potentially involved in the development of AMME contiguous gene deletion syndrome.