Sixty-four patients with Brachmann-de Lange syndrome: a survey

We surveyed 64 individuals with the diagnosis of Brachmann-de Lange syndrome (BDLS) to determine the natural course and cause of the disorder. The 64 individuals were ascertained through membership in a national organization, the Cornelia de Lange Syndrome (CDLS) Foundation, comprised of families who have a relative with BDLS. We surveyed 64 families by questionnaire and personally examined 24 of the 64. Our data suggest that lower birth weight correlates with a more severe phenotype, specifically including severe upper limb malformations and greater psychomotor retardation. The lower birth weight group showed a significant excess of females. The miscarriage rate was normal and there were no recurrences reported in the 64 families we surveyed. Major management problems included feeding problems and projectile vomiting, behavioral problems including frequent tantrums, hearing and dental difficulties, and recurrent respiratory tract infections. The oldest, teenaged subjects in our study entered puberty; although pregnancy has not been reported in the syndrome, it is likely that people with BDLS are fertile. Though most BDLS children reared at home survive through adolescence, a significant degree of psychomotor retardation and difficult medical management problems still occur.     

Syndrome of microcephaly,Brachmann–de Lange-like facial changes,severe metatarsus adductus,and developmental delay: Mild Brachmann-de Lange syndrome?

We report on 4 individuals (3 sibs and their father) with a syndrome of growth retardation, microcephaly, minor facial anomalies reminiscent of a mild Brachmann–de Lange syndrome (BDLS), severe metatarsus adductus, developmental delay, and unusual dermatoglyphics. The syndrome, which seems to be inherited as an autosomal dominant trait with variable expressivity, resembles mild BDLS.     

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.     

Syndrome of microcephaly, Brachmann-de Lange-like facial changes, severe metatarsus adductus, and developmental delay: mild Brachmann-de Lange syndrome?

We report on 4 individuals (3 sibs and their father) with a syndrome of growth retardation, microcephaly, minor facial anomalies reminiscent of a mild Brachmann-de Lange syndrome (BDLS), severe metatarsus adductus, developmental delay, and unusual dermatoglyphics. The syndrome, which seems to be inherited as an autosomal dominant trait with variable expressivity, resembles mild BDLS.     

Growth manifestations in the Brachmann-de Lange syndrome

We have obtained serial measurements on 180 patients with clinically confirmed Brachmann-de Lange syndrome (BDLS) in order to derive standard growth curves. The patients were evaluated in our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation, a support group for families of affected individuals. The data were obtained from the records of pediatricians, other physicians, schools and parents, as well as from personal examination on each of these patients at least once, often periodically. The growth curves include height, weight and head circumference measurements from birth through adulthood. Prenatal growth and birth weights are below the 5th centile in most (68%) cases, with an average birth weight of 2,277 g. Growth persists below the normal curves in most of the patients throughout life. Height velocity is equal to the normal range but there is slower pubertal growth. Weight velocity is below the normal range throughout life until late adolescence. Average head circumference remains below the second centile. Thin body habitus coupled with slow growth and proportionate small stature is a manifestation of the syndrome, but is commonly mistaken for failure to thrive. © 1993 Wiley-Liss, Inc.     

Mild mental retardation with classic somatic phenotype in the Brachmann-de Lange syndrome

Severe Mental retardation is the most handicapping disability for individuals with Brachmann-de Lange syndrome (BDLS). Reports of higher functioning patients with suspected BDLS have invariably described those with a “mild” BDLS somatic phenotype. Here we report on 2 high-functioning females, ages 3.7 and 10.6 years, with the classic BDLS somatic phenotype, i.e., all growth parameters at 4–5 standard deviations bellow the mean prenatally and postnatally. These 2 patients serve to extend the spectrum of classic BDLS to include cognitive function in the mild-to -moderate range of mental retardation. © 1993 Wiley-Liss, Inc.     

Neonatal-onset panhypopituitarism in a girl with Brachmann-De Lange syndrome

We report on a girl with recurrent hypoglycemia since age 2 days and severe impairment of physical and neurological development. Panhypopituitarism was recognized at age 5 months. The diagnosis of Brachmann-De Lange syndrome (BDLS) was also made. Replacement therapy has avoided further episodes of hypoglycemia, improved growth, and allowed partial psychomotor catch-up. Though we are not aware of any other report of panhypopituitarism in patients with BDLS, we suggest that hormonal derangement may play a role in the manifestations of this syndrome.     

Variability of the Brachmann-de Lange Syndrome

Brachmann-de Lange syndrome (BDLS) is a relatively common multiple congenital anomaly/mental retardation syndrome, whose cause is unknown. The clinical variability of this condition is well-known. Recently some reports suggested the possible existence of a mild BDLS phenotype. We report on 30 patients in whom a diagnosis of BDLS was made or strongly suspected in 12 different Italian hospitals. Based on clinical evaluation we divided them into two groups, classical and mild BDLS cases. We compare the clinical data of these patients and we discuss the problems which arise in trying to define clear criteria of distinction between these two groups. © 1993 Wiley-Liss, Inc.     

Fetal biometry in the Brachmann-de Lange syndrome

The Brachmann-de Lange syndrome (BDLS) is diagnosed in children on the basis of a distinctive clinical phenotype which includes retarded physical growth. Because there are no genetic or biochemical tests at present, the antenatal detection of the syndrome may depend upon identification of some aspect of the phenotype in the fetus using ultrasound imaging. We studied the growth of 23 subsequently diagnosed fetuses with the BDLS using standard biometric parameters defined by prenatal ultrasound imaging. Sonographic studies were obtained through a national parents' group, the Cornelia de Lange Syndrome Foundation. Assessment of fetal growth was made using four standardized measurements: the biparietal diameter, head circumference, femur length, and abdominal circumference. These values were compared to established tables of normal fetal growth and established rations of fetal body proportions. The cross-sectional growth curve derived using all measurements collected as a composite group indicates that growth retardation would be first detected as early as 25 weeks. In five fetuses with measurements both before and after 25 weeks of gestation, longitudinal growth curves indicated that the diagnosis of “small for gestational age” would have been suggested between 20 and 25 weeks. The mean fetal weight estimates closely followed the fifth centile curve of normal fetuses both before and after 25 weeks. Cephalic indices in BDLS fetuses indicated either frank brachycephaly (25%), or were at the upper portion of the normal range. Femur lengths were relatively short (less than 90% of their expected length ) in 4 of the 11 fetuses where such information could be obtained. BDLS fetuses demonstrate early and symmetric intrauterine growth retardation. We conclude that fetal biometry can provide a valuable index in the assessment of a pregnancy suspected to be at risk for a severely affected BDLS child. © 1993 Wiley-Liss, Inc.     

Dental Findings in Cornelia De Lange Syndrome

Cornelia de Lange syndrome is a congenital disease, basically characterized by psychomotor retardation associated with a series of malformations, including mainly skeletal, craniofacial deformities together with gastrointestinal and cardiac malformations. There is no definitive biochemical or chromosomal marker for the prenatal diagnosis of this syndrome. We actually want to present the case of a 10-year-old patient, who was admitted to our clinic for dental pain. The patient had the symptoms of Cornelia de Lange syndrome. During the oral examination of this patient, the patient was found to have the typical symptoms of Cornelia de Lange syndrome, such as micrognathia and delayed eruption in conjunction with the symptoms of the Hutchinson''s syndrome, which had never been reported before.     

De Lange syndrome: subjective and objective comparison of the classical and mild phenotypes.

Classical de Lange syndrome presents with a striking face, pronounced growth and mental retardation, and variable limb deficiencies. Over the past five years, a mild variant has been defined, with less significant psychomotor retardation, less marked pre- and postnatal growth deficiency, and an uncommon association with major malformations, although mild limb anomalies may be present. We have evaluated 43 subjects with de Lange syndrome, 30 with classical features, aged from birth to 21 years, and 13 with the mild phenotype, aged from 18 months to 30 years. In addition to assessment of gestalt and facial change with time, detailed craniofacial measurements have been obtained on each subject and composite pattern profiles compiled. The characteristic face of classical de Lange syndrome is present at birth and changes little throughout life, although there is some lengthening of the face with age and the jaw becomes squared. In mild de Lange syndrome, the characteristic classical appearance may be present at birth, but in some subjects it may be two or three years before the typical face is obvious. In general, the overall impression is less striking, perhaps because of increased facial expression and greater alertness. With age, the face loses the characteristic appearance, the nasal height increases, the philtrum does not seem as long, and the upper vermilion is full and everted, although the crescent shaped mouth with downturned corners remains. Eyebrows may be full and bushy. Objective comparison of the face in mild and classical de Lange syndrome, through the use of craniofacial pattern profiles, shows marked similarity of patterns at 4 to 9 years; both groups have microbrachycephaly, but the individual dimensions of the mild group are slightly closer to normal than their classical counterparts. The correlation coefficient is high (0.83). In the adult groups, similarity of patterns remains but is less marked. The normalisation of scores in the mild group is more dramatic. The correlation coefficient is lower (0.71). These objective findings substantiate clinical impressions of a phenotypic dichotomy. Early in life, the craniofacial features in mild de Lange syndrome may be indistinguishable from the classical phenotype and alternative discriminators must be sought in order to identify those subjects in whom the prognosis is more optimistic. Birth weight of more than 2500 g and absence of major limb anomalies may help in this regard.     

Metacarpophalangeal pattern profile analysis in Brachmann-de Lange syndrome

We analyzed the metacarpophalangeal pattern profile (MCPP) of 19 individuals with Brachmann-de Lange syndrome (BDLS) and calculated a mean syndrome profile. Fourteen of 19 individuals with BDLS had significant positive correlations which indicated clinical homogeneity. Discriminant analysis of individuals with BDLS compared with a sample of normal individuals produced a correct classification rate of 100% based on a function of 2 MCPP variables that may provide a useful tool for assisting in the diagnosis of BDLS. An average pattern variability index calculated for the BDLS patients was 1.9 indicating an abnormal hand pattern in this syndrome. © 1993 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome (BDLS) with asymmetry and skin pigmentary anomalies: a result of mosaicism for a putative bdls gene mutation?

Brachmann-de Lange syndrome (BDLS, OMIM 122470) is a rare malformation syndrome characterized by mental retardation, short stature, limb abnormalities, and a distinctive craniofacial appearance. There is wide clinical variability and mildly affected patients are common. The genetic basis of BDLS and the reasons for its phenotypical variability are still unknown. We report on a patient with mild BDLS and the unusual findings of asymmetric growth of one body half and irregularly shaped pigmentary anomalies of the skin. These two traits have not been previously described in BDLS but have been associated with phenomena of genetic mosaicism in other conditions. We suggest that this patient's phenotype could be the result of mosaicism for a mutation or submicroscopic deletion affecting one or several genes responsible for BDLS.     

Developmental data on individuals with the Brachmann-de Lange syndrome

One hundred twenty-two patients with clinically confirmed Brachmann-de Lenge syndrome (BDLS) were evaluated developmentally. Recruitment was made from our genetics department and through meetings of the Cornelia de Lange Syndrome Foundation parent support group. Developmental information was obtained from records of physicians, schools and developmental centers, or from parents on each of the 122 individuals, allowing division in to four groups for study: group 1 (n = 48) underwent formal developmental assessments, which generated intelligence or developmental quotients, and had a completed parental questionnaire with specific developmental questions regarding ages of skills mastered; group II (n = 23) had additional developmental records available without formal testing, as well as the questionnaire; group III (n = 22) had a only a completed questionnaire; and group IV (n = 29) had formal developmental testing or other developmental records but no available questionnaire. These data were analyzed in order to be able to predict attainable psychomotor development. Average scores on formal testing were found to be in the mild to moderate level of mental retardation, ranging from below 30 to 85, with an average intelligence quotient of 53, higher than previously reported. Visual-spatial memory and perceptual organization skills were found to be strengths. Younger individuals born before 1980 demonstrated higher scores on testing. Early intervention appears to play a major role in the level of developmental achievement. © 1993 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome with normal IQ

The Brachmann-de Lange syndrome is a disorder with a high degree of clinical variability, generally associated with moderate to severe mental retardation. To date, 7 previous cases of Brachmann-de Lange syndrome with normal intelligence (IQ > 70) have been described. We report the eighth case of Brachmann-de Lange syndrome with normal intelligence. In reviewing thr literature, consistent clinical menifestations seen in these 8 patients that are of prognostic value are the absence of significant limb anomalies and birth weight > 2,500 g. © 1993 Wiley-Liss, Inc.     

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.     

Partial duplication of 3q (q25.1→q26.1) without the Brachmann-de Lange phenotype

Partial duplications of chromosome 3 have previously been reported to have phenotypic characteristics similar to Brachmann-de Lange syndrome (BDLS). We present the case of a 13-Year-old girl with an apparent duplication in the 3q25.1→q26.1 region but none of the manifestations commonly seen in BDLS. The chromosome 3 duplication was confirmed with a FISH painting probe of the involved region. These results suggest that the region critical for Brachmann-de Lange syndrome is not within the duplicated region of 3q25.1→q26.1. © 1993 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome: Pre- and postnatal findings

Brachmann-de Lange syndrome (BDLS) is a well-delineated and relatively common syndrome. However, prenatal diagnosis has never been reported, even if in some cases ultrasonography demonstrated one or more manifestations of the syndrome. We report on 3 cases: in the first 2 cases, prenatal ultrasonography demonstrated some signs of the condition. The third represents, to our knowledge, the first prenatal diagnosis of BDLS. We also present a review of the literature concerning pre- and postnatal findings in this syndrome. © 1996 Wiley-Liss, Inc.     

Brachmann-de Lange syndrome: Autosomal dominant inheritance and male-to-male transmission

We report on familial occurrence of the Brachmann-de Lange syndrome (BDLS): a mildly affected father and his severely affected son and daughter who have different mothers. Both children are severely affected while the father has a much milder but definite BDLS phenotype. Our report documents the third example of male-to-male transmission and adds to the argument against exclusively maternal transmission in familial cases. In addition, our findings illustrate the occurrence of severe manifestations in cases of familial BDLS. © 1996 Wiley-Liss, Inc.     

Epileptic encephalopathy and amelogenesis imperfecta: Kohlschütter-Tönz syndrome

Kohlschütter–Tönz syndrome is a rare genetic disorder with epilepsy, psychomotor regression, and a severe enamel defect with yellow or brownish discoloration of the teeth. The first affected family was described in 1974, and 25 patients in 11 families have been reported until now. Inheritance is autosomal recessive. Epilepsy usually starts within the first or second year of life. All affected individuals show a psychomotor regression after onset of epilepsy or a developmental delay from birth on. Clinical course and disease severity are variable even within families. There are no known biochemical or other diagnostic markers of the condition. Very recently it has been shown that the condition is caused by mutations in the gene ROGDI but molecular data have only been reported for three families. It remains to be seen whether Kohlschütter–Tönz syndrome has the same molecular basis in all affected individuals.