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.

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.

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.

The neuropathology of Williams syndrome. Report of a 35-year-old man with presenile beta/A4 amyloid plaques and neurofibrillary tangles.

OBJECTIVE: To study neuropathologically Williams syndrome in a 35-year-old patient. METHODS: Sections from multiple regions of the brain were examined with luxol fast blue and hematoxylineosin staining, and selected sections were stained with the silver impregnation technique (Bielschowsky technique) and Congo red. In addition, immunohistochemistry with monoclonal antibodies against glial fibrillary acidic protein, beta/A4 amyloid, paired helical filaments, and phosphorylated tau protein was performed on cortical, hippocampal, amygdaloid, and basal ganglian sections. RESULTS: No specific macroscopic or microscopic abnormalities were recognized that are specific for Williams syndrome. The histopathologic examination did, however, demonstrate the presence of Alzheimer-type changes, including beta/A4 amyloid-containing senile plaques and scattered neurofibrillary tangles in neocortex and medial temporal lobe structures (entorhinal cortex, CA1 area of the hippocampus, and amygdala). Plaques were most numerous in the amygdala (7/mm2) and in the entorhinal cortex (4/mm2). Neurofibrillary tangles were less numerous (< 1/mm2), except in the hippocampus, where approximately 2/mm2 were found. CONCLUSIONS: To our knowledge, ours represents the first neuropathologic description of a patient with Williams syndrome. Although Williams syndrome is usually sporadic, familial cases have been reported along with candidate chromosomal loci. If our findings are confirmed in additional patients with Williams syndrome, they may provide clues to other factors that are important in the pathogenesis of senile plaques (with beta/A4 amyloid deposition) and neurofibrillary tangles.

Phenotypic heterogeneity of spinal muscular atrophy mapping to chromosome 5q11.2-13.3 (SMA 5q).

We made phenotypic analysis of 14 families with spinal muscular atrophy (SMA) linking to chromosome 5q11.2-13.3 (SMA 5q), and 2 that may not map to this locus, to assess clinical symptoms among SMA families known to result from mutation at the identical gene/locus. Although the current number of families is still small, the correlation of clinical phenotype and molecular genotype supports 2 observations. First, SMA mutations at the 5q locus present with a broad continuum of clinical abnormalities, and 2nd, the single clearly unlinked family presents with an unusual phenotype characterized by relatively late onset and early death. Thus, there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q-ie, no clear cases of nonallelic heterogeneity. Analysis of SMA 5q families supports the view that, with certain exceptions, there is little phenotypic intrafamilial variability. When families were ranked by severity of disease there was a strong correlation with age of onset. Onset within the 1st few months was associated with early death, but not in all cases. With rare exception, onset after 1 year of age was associated with less severe disease and greater longevity.

Type III tracheal agenesis with familial tetralogy of Fallot and absent pulmonary valve syndrome.

We describe a female infant born at 33 weeks gestation diagnosed postnatally with a previously unreported phenotype consisting of Type III tracheal agenesis plus tetralogy of Fallot with absent pulmonary valve. She was delivered to a mother who had the same congenital heart malformation, but no detectable tracheal abnormality. We discuss possible etiologies of these malformations.

Renal findings in 40 individuals with Williams syndrome.

We tabulated the frequency of renal abnormalities in 40 Williams syndrome individuals presenting for medical and/or developmental assessment to a multi-disciplinary Williams syndrome program. The average age at time of assessment was 7 2/12 years. Seven individuals (7/40 = 18%) had abnormalities detected, including nephrocalcinosis = 2; marked asymmetry in kidney size = 2; small kidneys = 1; solitary kidney = 1; and pelvic kidney = 1. Renal function was also assessed. Two individuals had evidence of renal dysfunction, one secondary to nephrocalcinosis and the second due to hypercalcemia and interstitial nephritis of unclear pathogenesis. We examined the frequency of renal artery stenosis in 9 individuals who underwent abdominal angiography during cardiac catheterization. We found unilateral or bilateral mild renal artery narrowing in 4 individuals and normal renal arteries in the remaining 5. Persistent hypertension occurred in only 2 individuals and did not correlate with renal artery status. We conclude that intrinsic renal anomalies, as well as problems secondary to hypercalcemia, occur with sufficient frequency to warrant baseline renal screening in all individuals with Williams syndrome.

Familial dup(5)(q15q21) associated with normal and abnormal phenotypes.

We studied a familial dup(5q) present in a phenotypically normal father and his monozygotic twin daughters with different abnormal phenotypes. High-resolution chromosome analysis suggested that the duplicated segment was of region q15-21, which seems to be the smallest dup(5q) reported thus far. This dup(5q) was confirmed by fluorescence in situ hybridization with a chromosome 5 painting library and 5q cosmid clones. The presence of the dup(5q) in a normal father suggested that the duplication itself may be harmless. The anomalies in the twins may be due to processes other than this chromosome change.

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.

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.

Acrocallosal syndrome: new findings.

We describe a 21-month-old girl with typical manifestations of the acrocallosal syndrome of craniofacial anomalies, agenesis of the corpus callosum, hallucal duplication, severe hypotonia, and psychomotor retardation. Our patient also had the Dandy-Walker malformation, imperforate anus with rectovaginal fistula, hypothalamic dysfunction with hypothyroidism and diabetes insipidus, thick, dysplastic pulmonic valve leaflets, central and obstructive apnea, and pulmonary hypertension. These findings add to the delineation of this syndrome.

Deletion of chromosome 2q24-q31 causes characteristic digital anomalies: case report and review.

We describe a newborn boy with multiple anomalies, including bilateral split foot and an interstitial deletion of chromosome 2 (q24.2-q31.1). Four additional cases in 2 families involving similar deletions have been reported. Bilateral digital anomalies of hands and feet were seen in all 5 cases, including a wide cleft between the first and second toes, wide halluces, brachysyndactyly of the toes, and camptodactyly of the fingers. Other common manifestations have included postnatal growth and mental retardation, microcephaly, down-slanting palpebral fissures, micrognathia, and apparently low-set ears. Bilateral digital anomalies were reported in 22 of 24 cases with deletions including at least part of region 2q24-q31. Digital anomalies were not prevalent in 18 patients with deletions of chromosome 2q not overlapping 2q24-q31. 2q31.1 appears to be the common deleted segment in all cases with significant digital anomalies, which implies the existence of one or more genes involved in distal limb morphogenesis in this region. HOXD13 and EVX2, located in the proximity of 2q31, were not deleted in our patient by Southern analysis. Bilateral digital malformations of the hands and feet associated with other anomalies should be evaluated by chromosome analysis focused at the 2q24-q31 region.

GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease.

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.

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.

Isolated congenital renal tubular immaturity in siblings.

This paper describes two cases of an unusual renal abnormality discovered in anuric siblings (one male, one female) who were born at 36 and 34 weeks of gestation and died of systemic complications secondary to severe pulmonary hypoplasia shortly after birth. Both gestations were complicated by marked oligohydramnios. Antenatal ultrasound examinations showed slightly enlarged kidneys in the first case and normal kidneys in the second case, with no evidence of hydronephrosis or cystic disease in either. With the exception of enlargement of the first infant's kidneys, autopsies revealed grossly unremarkable kidneys and ureters. Microscopy, however, demonstrated increased glomerulogenesis with normal glomeruli and global immaturity of renal tubules and ducts without concomitant features of dysplasia. Immunoperoxidase staining for epithelial membrane antigen revealed the immaturity or complete absence of proximal convoluted tubules. This precise constellation of findings had not been described previously. One other similar family has been documented in a report implicating genetic factors. In the present cases, the possibility of a cocaine-associated etiology is also addressed.

Neurologic findings in children and adults with Williams syndrome.

Twenty-four children with Williams syndrome underwent systematic neurologic evaluations. Abnormalities of mental status, motor coordination, tone, and gait were most prevalent. Tone abnormalities varied as a function of age, with younger children frequently exhibiting decreased tone and older subjects almost exclusively having increased tone. The gait and coordination abnormalities persisted among older subjects, indicating that they were not simply maturational problems. Physicians caring for such youngsters need to be aware that a variety of neurologic abnormalities are common in Williams syndrome and may change or progress over time. Neurologic examinations that reveal findings beyond the typical pattern that we report may raise suspicion for added neurologic insult and warrant further investigation.

Association of Chiari I malformation and Williams syndrome.

Two Williams syndrome patients are presented who had neurologic symptoms secondary to Chiari malformation type I. Both patients had many of the well-known medical problems found in Williams syndrome. In addition, Patient 1 developed headache, diplopia, and tinnitus at 26 years of age. Neurologic examination revealed intermittent nystagmus and brisk reflexes. Magnetic resonance imaging demonstrated Chiari malformation type I; neurologic symptoms abated following surgery. Patient 2 had a normal neurologic examination at 2 years of age except for hyperreflexia and tight heel cords. At age 10 years, she had generalized contractures, decreased strength and wasting of hand musculature, and hyperreflexia. Magnetic resonance imaging documented Chiari malformation type I. Both patients have significant dysphagia and fusion of cervical spine segments noted on radiography. Morphometric analyses of intracranial contents based on midsagittal magnetic resonance images were performed. This analysis suggests that, compared to age-matched controls, the posterior fossa size is selectively diminished in Williams syndrome, whereas the cerebellum is normal in size. This "mismatch" between the size of the posterior fossa bony compartment and its neural contents may place Williams syndrome patients at high risk for developing Chiari malformation type I.