On the variability of the Brachmann-de Lange syndrome in seven patients

The results of the clinical and radiographic study of 7 patients support the view of a unimodal and rather narrow phenotypic spectrum in the Brachmann-de Lange syndrome (BDLS) and reject the existence of a “classic” type of patient and a “mild phenotype” without upper limb defects who survive with moderate to severe mental retardation. Similarity among all patients is greater than their phenotypic differences. Strict clinical definition of the syndrome warrants easier access to the still unknown cause, most probably a single gene mutation with autosomal dominant inheritance. © 1993 Wiley-Liss, Inc.     

Ultrasonographic and clinical appearance of a 22‐week‐old fetus with Brachmann‐de Lange syndrome

The diagnosis Brachmann‐de Lange or Cornelia‐de Lange syndrome is based on the characteristic facial appearance and other malformations. Prenatal ultrasonographic diagnosis has been made occasionally usually confirmed by clinical photographs of third trimester fetuses with distinctly recognizable hair anomalies (synophrys, low anterior and posterior hairlines, and hypertrichosis). However, at 22 weeks of gestation, these highly characteristic signs fail to support the clinical diagnosis. We report on pre‐ and post‐natal findings in a 22‐week‐old female fetus with Brachmann‐de Lange syndrome. The facial Gestalt was already characteristic and the associated upper limb malformations (bilateral monodactyly and ulnar agenesis) supported the diagnosis. The prenatal ultrasound images demonstrated a grossly abnormal facial profile (a protruding and overhanging upper lip and severe retrognathia) highly suggestive of Brachmann‐de Lange syndrome. The recurrence risk is estimated &#1%. The recognition of Brachmann‐de Lange syndrome in second trimester fetuses is essential for genetic counselling and reassurance of parents contemplating future reproduction. © 2001 Wiley‐Liss, Inc.     

Autosomal dominant inheritance of Brachmann-de Lange syndrome

A mother with mild phenotype and her severely affected son, both with classic manifestations of Brachmann-de Lange syndrome (BDLS), are described. This documented mother-to-child transmission supports the hypothesis of autosomal dominant transmission with intrafamilial variability. Known cases of BDLS with autosomal dominant inheritance are reviewed. Although most cases of BDLS are sporadic, a careful evaluation of parents of affected children is important for appropriate genetic counseling. © 1996 Wiley-Liss, Inc.     

Clinical variability within Brachmann-de Lange syndrome: A proposed classification system

Seven patients, including two sibs, with the Brachmann-de Lange syndrome (BDLS) are presented as representative of the different types of BDLS in a proposed classification system. Type I (“classic”) patients have the characteristic facial and skeletal changes of BDLS using the criteria in the diagnostic index of Preus and Rex. Type I is distinguished from the other subtypes by prenatal growth deficiency (< 2.5 S.D. below mean for gestation) becoming more severe postnatally (< 3.5 S.D. below the mean), moderate to profound psychomotor retardation, and major malformations which result in severe disability or death. Type II (“mild”) BDLS patients have similar facial and minor skeletal abnormalities to those seen in type I; however, these changes may develop with time or may be partially expressed. Patients with type II BDLS are distinguished from those with other types by mild to borderline psychomotor retardation, less severe pre-and postnatal growth deficiency, and the absence of (or loss severe) major malformations. Behavioral problems can be a significant clinical problem in type II BDLS. Type III (“phenocopies”) BDLS includes patients who have phenotypic manifestations of BDLS which are causally related to chromosomal aneuploidies or teratogenic exposures. © 1993 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome. Delineation of the clinical phenotype

A total of 31 cases previously diagnosed as having Brachmann-de Lange syndrome were ascertained and examined, of which 11 were thought to have been misdiagnosed. Of those correctly diagnosed, there appeared to be a phenotypic dichotomy with classical and mild cases. Those facial findings of greatest diagnostic value were the combination of the characteristic eyebrows, long philtrum, thin lips and crescent-shaped mouth. The characteristic eyebrows were neat, well defined and arched as though they had been pencilled. This combination of anomalies was absent in postpubertal males but not in postpubertal females. Facial abnormalities most likely to lead to incorrect use of the eponym were hypertrichosis, synophrys, and bushy eyebrows. © 1993 Wiley-Liss, Inc.     

The de Lange syndrome. Report of 15 cases

Fifteen cases of the de Lange syndrome are presented. Personal and family histories, clinical features, detailed radiological findings, laboratory data, chromosome studies and dermatoglyphic patterns are reported. A Negro patient and his autopsy findings are described. Radiological diagnostic features are stressed; in particular, the combined presence of a hypoplastic middle phalanx of the index fingers and variable short metatarsal appear to be two additional features which are diagnostically helpful. The etiology of the syndrome is unknown; however, there is some evidence to suggest a genetic basis. The literature is briefly reviewed.     

Novel mosaic variants in two patients with Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a dominantly inherited developmental disorder caused by mutations in genes that encode for either structural (SMC1A, SMC3, RAD21) or regulatory (NIPBL, HDAC8) subunits of the cohesin complex. NIPBL represents the major gene of the syndrome and heterozygous mutations can be identified in more than 65% of patients. Interestingly, large portions of these variants were described as somatic mosaicism and often escape standard molecular diagnostics using lymphocyte DNA.Here we discuss the role of somatic mosaicism in CdLS and describe two additional patients with NIPBL mosaicism detected by targeted gene panel or exome sequencing. In order to verify the next generation sequencing data, Sanger sequencing or pyrosequencing on DNA extracted from different tissues were applied. None of the pathogenic variants was originally detected by Sanger sequencing on blood DNA.Patient 1 displays an unusual combination of clinical features: he is cognitively only mildly affected, but shows severe limb reduction defects. Patient 2 presents with a moderate phenotype. Interestingly, Sanger sequencing analysis on fibroblast DNA of this patient did not detect the disease-causing variant previously observed on the same DNA sample by exome sequencing. Subsequent analyses could confirm the variants by Sanger sequencing on buccal mucosa DNA. Notably, this is the first report of a higher mutational load in buccal mucosa than in fibroblast cells of a CdLS patient.Detection of low-level mosaicism is of utmost importance for an accurate molecular diagnosis and a proper genetic counseling of patients with a clinical diagnosis of CdLS. Next-generation sequencing technologies greatly facilitate the detection of low-level mosaicism, which might otherwise remain undetected by conventional sequencing approaches.     

de Lange syndrome: A clinical review of 310 individuals

Three hundred ten individuals with a clinical diagnosis of de Lange syndrome were seen and examined in conjunction with the parent support group. One hundred thirty-four males and 176 females whose ages ranged from birth to 37 years made up the study group. Examination findings were recorded for those features described by de Lange in her original report of the syndrome to determine the frequency and significance of each. In addition, questionnaires were completed by 128 of these families and medical, growth and developmental records were collected. The clinical diagnosis seems best supported by the facial features of the syndrome including the long eyelashes and confluent eyebrows (synophrys), although additional characteristics are needed. Only 27% had the upper limb deficiencies commonly associated with the syndrome. Growth was retarded in nearly all individuals, often of prenatal onset. Medical problems occurred frequently and most often involved the eye and ear, as well as the cardiac and gastrointestinal systems. Of 14 deaths, almost half were secondary to cardiac or gastrointestinal complications. The recurrence risk in 377 sibs of the patients was calculated to be less than 1%. Although development lagged significantly in speech, most individuals developed good self-help skills. The study demonstrated a higher proportion of patients affected mildly with the syndrome than is commonly appreciated. This underscores the importance of early recognition and appropriate medical and developmental support. © 1993 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome: Diagnostic difficulties posed by the mild phenotype

We described 4 patients with facial changes of Brachmann-de Lange syndrome but without limb defects. Mental retardation ranged from moderate to severe and the degree of Prenatal and postnatal growth deficiency was variable. These patients exemplify the diagnostic difficulties and counseling dilemmas posed by the mild Brachmann-de Lange phenotype. The relationship of the mild phenotype to the full syndrome will not be understood until the pathogenetic or causal factor(s) are delineated. © 1993 Wiley-Liss, Inc.     

Three‐year‐old girl with partial trisomy 4p and partial monosomy 8p with resemblance to Brachmann‐de Lange syndrome—another locus for Brachmann‐de Lange syndrome on 4p?

We describe a 3‐year‐old girl with partial trisomy 4p and partial monosomy 8p who had prenatal and postnatal growth retardation, mental retardation, no speech development, mild synophrys, hirsutism, apparently low‐set ears, dysphonic hoarse voice, hyperactivity, and small hands with proximal placement of the thumbs. She had recurrent lung infections, due to earlier aspiration and immune deficiency (chronic granulomatous disease). Cytogenetic findings in this and other cases with suggestive phenotype may point to an additional locus for Brachmann‐de Lange phenotype. Am. J. Med. Genet. 91:180–184, 2000. © 2000 Wiley‐Liss, Inc.     

Causes of death and autopsy findings in a large study cohort of individuals with Cornelia de Lange syndrome and review of the literature

To identify causes of death (COD) in propositi with Cornelia de Lange syndrome (CdLS) at various ages, and to develop guidelines to improve management and avoid morbidity and mortality, we retrospectively reviewed a total of 426 propositi with confirmed clinical diagnoses of CdLS in our database who died in a 41-year period between 1966 and 2007. Of these, 295 had an identifiable COD reported to us. Clinical, laboratory, and complete autopsy data were completed on 41, of which 38 were obtainable, an additional 19 had autopsies that only documented the COD, and 45 propositi had surgical, imaging, or terminal event clinical documentation of their COD. Proband ages ranged from fetuses (21-40 weeks gestation) to 61 years. A literature review was undertaken to identify all reported causes of death in CdLS individuals. In our cohort of 295 propositi with a known COD, respiratory causes including aspiration/reflux and pneumonias were the most common primary causes (31%), followed by gastrointestinal disease, including obstruction/volvulus (19%). Congenital anomalies accounted for 15% of deaths and included congenital diaphragmatic hernia and congenital heart defects. Acquired cardiac disease accounted for 3% of deaths. Neurological causes and accidents each accounted for 8%, sepsis for 4%, cancer for 2%, renal disease for 1.7%, and other causes, 9% of deaths. We also present 21 representative clinical cases for illustration. This comprehensive review has identified important etiologies contributing to the morbidity and mortality in this population that will provide for an improved understanding of clinical complications, and management for children and adults with CdLS.     

Mutational and phenotypic spectra of KCNE1 deficiency in Jervell and Lange‐Nielsen Syndrome and Romano‐Ward Syndrome

KCNE1 encodes a regulatory subunit of the KCNQ1 potassium channel‐complex. Both KCNE1 and KCNQ1 are necessary for normal hearing and cardiac ventricular repolarization. Recessive variants in these genes are associated with Jervell and Lange‐Nielson syndrome (JLNS1 and JLNS2), a cardio‐auditory syndrome characterized by congenital profound sensorineural deafness and a prolonged QT interval that can cause ventricular arrhythmias and sudden cardiac death. Some normal‐hearing carriers of heterozygous missense variants of KCNE1 and KCNQ1 have prolonged QT intervals, a dominantly inherited phenotype designated Romano‐Ward syndrome (RWS), which is also associated with arrhythmias and elevated risk of sudden death. Coassembly of certain mutant KCNE1 monomers with wild‐type KCNQ1 subunits results in RWS by a dominant negative mechanism. This paper reviews variants of KCNE1 and their associated phenotypes, including biallelic truncating null variants of KCNE1 that have not been previously reported. We describe three homozygous nonsense mutations of KCNE1 segregating in families ascertained ostensibly for nonsyndromic deafness: c.50G>A (p.Trp17*), c.51G>A (p.Trp17*), and c.138C>A (p.Tyr46*). Some individuals carrying missense variants of KCNE1 have RWS. However, heterozygotes for loss‐of‐function variants of KCNE1 may have normal QT intervals while biallelic null alleles are associated with JLNS2, indicating a complex genotype‐phenotype spectrum for KCNE1 variants.     

Expanding the clinical spectrum of the ‘HDAC8‐phenotype’ – implications for molecular diagnostics,counseling and risk prediction

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin‐related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS‐overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X‐inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.     

Search for genomic imbalances in a cohort of 24 Cornelia de Lange patients negative for mutations in the NIPBL and SMC1L1 genes

Cornelia de Lange syndrome (CdLS) is a rare, multiple congenital anomaly/mental retardation syndrome characterized by varied clinical signs including facial dysmorphism, pre- and post-natal growth defects, small hands and malformations of the upper limbs. Established genetic causes include mutations in the NIPBL (50-60%), SMC1L1 and SMC3 (5%) genes. To detect chromosomal rearrangements pointing to novel positional candidate CdLS genes, we used array-CGH to analyze a subgroup of 24 CdLS patients negative for mutations in the NIPBL and SMC1L1 genes. We identified three carriers of DNA copy number alterations, including a de novo 15q26.2-qter 8-Mb deletion, and two inherited 13q14.2-q14.3 1-Mb deletion and 13q21.32-q21.33 1.5-Mb duplication, not reported among copy number variants. The clinical presentation of all three patients matched the diagnostic criteria for CdLS, and the phenotype of the patient with the 15qter deletion is compared to that of both CdLS and 15qter microdeletion patients.