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PubMed1998

Comparison of clinical-radiological and molecular findings in hypochondroplasia.

Hypochondroplasia is an autosomal dominant skeletal dysplasia characterized by disproportionate short stature. A mutation (N540K) in the fibroblast growth factor receptor 3 (FGFR3) gene was described in some patients with this condition. The aims of the study were to identify the frequency of the FGFR3 gene mutation, to define the salient clinical and radiological abnormalities of the affected subjects, and to verify the contribution of molecular findings to the clinical and radiological definition of hypochondroplasia. Based on the most common radiological criteria, we selected 18 patients with a phenotype compatible with hypochondroplasia. Height, sitting height, and cranial circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis, and left hand were also obtained. The presence of the N540K mutation was verified by restriction enzyme digestions. Half of our patients carried the N540K mutation. Although similar in phenotype to the patients without the mutation, they showed in addition relative macrocephaly. The association of the unchanged/narrow interpedicular distance with the fibula longer than the tibia was more common in patients with gene mutation. Although we did not find a firm correlation between genotype and phenotype, in our study the N540K mutation was most often associated with disproportionate short stature, macrocephaly, and with radiological findings of unchanged/narrow interpedicular distance and fibula longer than tibia.

Adolescent↗

PubMed2001

Prenatal diagnosis and genetic analysis of type I and type II thanatophoric dysplasia.

Thanatophoric dysplasia (TD) is one of the most common neonatal lethal skeletal dysplasias. Prenatal sonographic and molecular genetic diagnoses of three cases of TD type I (TD1) and one case of TD type II (TD2) are presented here. Two fetuses of TD1 were characterized by polyhydramnios, macrocephaly, short limbs, a narrow thoracic cage and curved short femora, but without a cloverleaf skull at 27 and 31 weeks' gestation, respectively. The third fetus with TD1 was, however, not associated with macrocephaly, polyhydramnios, chest narrowing and severe femoral bowing on prenatal ultrasound at 18 weeks' gestation. The TD2 fetus was characterized by polyhydramnios, short limbs, a narrow thoracic cage, straight short femora, hydrocephalus and a cloverleaf skull at 24 weeks' gestation. Three-dimensional ultrasound was able to enhance the visualization of thickened, redundant skin folds and craniofacial and limb deformities associated with TD. Molecular analysis of the fibroblast growth factor receptor 3 (FGFR3) gene by restriction enzyme digestion analysis and direct sequencing using cultured amniotic fluid cells or cord blood cells revealed a missense mutation of 742C-->T (Arg248Cys) in all cases with TD1 and a missense mutation of 1948A-->G (Lys650Glu) in the case with TD2. The present report shows that adjunctive applications of molecular genetic analysis of the FGFR3 gene and three-dimensional ultrasound are useful for prenatal diagnosis of TD.

Adult↗

PubMed1983

Ruvalcaba-Myhre-Smith syndrome: a case with probable autosomal-dominant inheritance and additional manifestations.

We report on a 7 1/2-year-old boy with macrocephaly, hamartomatous intestinal polyps, and café-au-lait spots on the penis. These abnormalities were reported in two other individuals thought to have the Sotos syndrome. We think that this triad of abnormalities represents a new disorder, the Ruvalcaba-Myhre-Smith syndrome. Prominent Schwalbe lines, prominent corneal nerves, and lipid storage myopathy also appear to be part of the syndrome. Macrocephaly, similar facial appearance, and a hamartomatous polyp in the mother suggest dominant inheritance.

Child↗

PubMed1984

Duplication of part of chromosome 1q: clinical report and review of literature.

We report a male infant with a 47,XY, + der(22),t(1;22)(q32;q11)pat karyotype. Thus, he has duplication of chromosomes 1(q32----qter) and 22(pter----q11). Six patients with dup 1(q32----qter) and eight with dup 1(q42----qter) have been described. These two groups of patients share several manifestations, including postnatal growth retardation; relative macrocephaly with widely separated sutures or large fontanelles; prominent forehead; highly arched palate; micrognathia; downward slant of the palpebral fissures; broad, flat nasal bridge; and apparently low-set, malformed ears. Although many of these abnormalities are nonspecific, partial duplication of 1q should be considered in infants with relative macrocephaly, large fontanelles, and downward slant of the palpebral fissures. Our patient had duplication of the part of chromosome 22 that may be associated with the clinically variable cat-eye syndrome. Patients with dup 22(pter----q11) may also have downward slant of the palpebral fissures, micrognathia, and apparently low-set, malformed ears. The structural gene locus for beta-glucosidase has been mapped to chromosome 1. beta-Glucosidase activity in fibroblasts from our patient was normal, and his parents' activities were not significantly different from those of control individuals. Therefore, either the locus for this enzyme is not present on 1(q32----qter) or the enzyme does not consistently show a substantial gene-dose effect.

Abnormalities, Multiple↗

PubMed1991

Beemer-Langer syndrome with manifestations of an orofaciodigital syndrome.

We report on an infant girl with hydrops, macrocephaly, high forehead, flat face, hypertelorism, broad nasal bridge, median cleft lip and alveolar ridge, grooved palate, accessory frenula, small tongue, milia, severe rib and limb shortness, brachydactyly, talipes equinovarus, Dandy-Walker malformation, accessory spleen, unfixed mesentery, ectopic pancreas, and renal cysts. This patient resembles seven previously reported patients with the Beemer-Langer syndrome, a distinct lethal short rib syndrome characterized by hydrops, markedly short ribs and limbs, median cleft lip with or without cleft palate, flat face, and macrocephaly. Polydactyly is usually absent. Our patient's oral anomalies suggest an orofaciodigital syndrome, but the severe rib and limb shortness distinguish it from those disorders.

Adult↗

PubMed1991

Relationship between head circumference and height in normal adults and in the nevoid basal cell carcinoma syndrome and neurofibromatosis type I.

Occipitofrontal circumference (OFC) was strongly correlated with height in 72 normal Caucasian men (r = 0.28, P = 0.018) and 78 women (r = 0.53, P less than 0.0001). OFC:height ratios were approximately normally distributed in each sex with a mean of 0.326 (standard deviation [sd] = 0.0139) in males and 0.335 (sd = 0.0177) in females. Relative macrocephaly (an OFC greater than the 95th centile for height) was seen in seven of nine probands with the nevoid basal cell carcinoma syndrome (NBCC), eight of 32 non-probands with NBCC, three of four neurofibromatosis type 1 (NF1) probands, and six of nine non-probands with NF1. Thirty-one percent of the non-proband NBCC cases had OFC less than the 50th centile for height, while none of the NF1 cases had this finding. Head size appears to be related to proband status in NBCC, while the evidence suggests that NF1 is a true macrocephaly syndrome. Objective detection of relative abnormalities in head size may aid in syndrome delineation and diagnosis.

Adult↗

PubMed1995

Trisomy 1q42 --> qter in a sister and brother: further delineation of the "trisomy 1q42 --> qter syndrome".

We report on a 22-year-old woman and her 21-year-old brother with mild mental retardation, long face, prominent forehead, retrognathia, and (relative) macrocephaly. At birth they were small for date, their length is now below the 10th centile. Chromosome analysis demonstrated a nearly pure trisomy 1q42 --> qter in both patients due to unbalanced segregation of a paternal reciprocal balanced translocation 46,XY,t(1;15) (q42;p11). This is the second report of a nearly pure trisomy 1q42 --> qter. When comparing the manifestations of our patients with those of other reported cases we conclude that the most characteristic clinical manifestations of this syndrome are macrocephaly, prominent forehead, micro/retrognathia, large fontanelle, intrauterine growth retardation, postnatal growth retardation, and mental retardation.

Adult↗

PubMed2004

Unbalanced cryptic 5p deletion/17p duplication identified by subtelomeric FISH in a family with a boy with chimerism and a balanced t(4;5).

The use of subtelomeric FISH probes has greatly supplemented conventional chromosome analysis in detecting cryptic anomalies in patients with mental retardation (MR), dysmorphic features, and congenital malformations. We report a 3-month-old boy who was diagnosed with ambiguous genitalia, dysmorphic features, and developmental delay. Standard chromosome studies on blood revealed a chimeric karyotype of 46,XY,t(4;5)(q31.1;q14)[46]/46,XX[4]. The boy had intra-abdominal gonads that were testicular in origin by biopsy. Multiple dysmorphic features, marked hypotonia, developmental delay, poor growth, and relative macrocephaly were noted on physical exam. His 2.5-year-old sister also presented with hypotonia, developmental delay, relative macrocephaly, and similar dysmorphic stigmata. In addition, she was diagnosed with several internal malformations. Her karyotype was 46,XX. Due to the striking phenotypic similarity, subtelomeric FISH studies were initiated in the siblings. In addition to the known balanced karyotypic abnormalities, the boy was found to have a derivative chromosome 5 with a 5pter deletion and a 17pter duplication. This cryptic abnormality was also detected in his sister. Chromosome analysis of the father revealed a subtle balanced t(5;17)(p15.31;p13.1) which was confirmed by subtelomeric FISH, whereas the mother's chromosome complement was normal. This familial constellation illustrates the usefulness of subtelomeric FISH in the diagnosis of cryptic chromosome abnormalities in patients for whom conventional karyotype does not disclose findings sufficient to explain the observed phenotypic anomalies.

Child, Preschool↗

PubMed2005

NSD1 mutations in Sotos syndrome.

Sotos syndrome is a genetic disorder characterized by a typical facial appearance, macrocephaly, accelerated growth, developmental delay, and a variable range of associated abnormalities. The NSD1 gene was recently found to be responsible for Sotos syndrome, and more than 150 patients with NSD1 alterations have been identified. A significant ethnic difference is found in the prevalence of different types of mutation, with a high percentage of microdeletions identified in Japanese Sotos syndrome patients and with intragenic mutations in most non-Japanese patients. NSD1 aberrations are rather specific for Sotos syndrome, but have also been detected in patients lacking one or more major criteria of the disorder, namely overgrowth, macrocephaly, and advanced bone age. Thus, new diagnostic criteria should be considered. Studies have reported different frequencies of mutations versus non-mutations in Sotos syndrome, thus indicating allelic or locus hetereogeneity. Although some authors have suggested genotype/phenotype correlations, further studies are needed.

Abnormalities, Multiple↗

PubMed1991

Lhermitte-Duclos disease and Cowden disease: a single phakomatosis.

Two unrelated patients with macrocephaly, seizures, and mild cerebellar signs had a dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Both also had autosomal dominant Cowden disease as evidenced by facial, oral, and acral papules. In the two families, 9 sibs demonstrated the mucocutaneous lesions, thyroid disease, breast tumors, and ovarian tumors compatible with the diagnosis of Cowden disease. Some of the sibs also showed various degrees of neurological signs such as macrocephaly, mental retardation, seizures, tremor, and dysdiadochokinesia. Magnetic resonance imaging scans of sibs of one family demonstrated megalencephaly and other mild abnormalities. The occurrence of these two rare disorders in single patients is more than a coincidence, and the clinical findings in the combined condition establishes it as a new phakomatosis.

Abnormalities, Multiple↗

PubMedDate not supplied

Indications for routine cranial ultrasound scanning in the nursery.

Cranial ultrasonography provides important diagnostic information in neonates. The clinical indications for routine scanning in newborn infants, however, are not established. The purpose of this study is to determine the incidence of cranial pathology detectable by ultrasound in certain clinical states in the neonate. We reviewed the scans and clinical states of 1,031 neonates born between April 1981 and February 1985. We found term infants with dysmorphic features to have the highest incidence of neuropathology (46%), followed by term infants born with macrocephaly (33%), preterm infants (26%), term infants with seizures (26%), and term infants with 1- and 5-min Apgar scores less than 7 (13%). We found a lower incidence (less than 5%) of abnormal CNS findings in the nonasphyxiated term infants with split sutures, cephalohematoma, abnormal neurologic examination, and idiopathic jitteriness. Based on our findings we have concluded that it is important to scan routinely all premature infants, term infants with dysmorphic features, macrocephaly, or seizure disorder, and infants with 1- and 5-min Apgar scores less than 7; routine scanning of term infants with split sutures, cephalohematoma, abnormal neurological examination, or idiopathic jitteriness is not indicated.

Apgar Score↗

PubMed2006

Perinatal findings and molecular cytogenetic analyses of de novo interstitial deletion of 9q (9q22.3-->q31.3) associated with Gorlin syndrome.

OBJECTIVES: To present the perinatal findings and the molecular cytogenetic analyses of a de novo interstitial deletion of 9q (9q22.3-->q31.3) associated with Gorlin syndrome. METHODS: Amniocentesis was performed at 18 weeks' gestation on a 27-year-old woman at a community hospital because of a high Down syndrome risk of 1/178, a low maternal serum alpha-fetoprotein (MSAFP) level of 0.66 multiples of the median (MoM), and a high maternal serum human chorionic gonadotrophin (MShCG) level of 3.13 MoM. The karyotype was initially determined to be 46,XY. However, fetal macrocephaly and overgrowth were found at 30 weeks' gestation. Postnatally, the infant manifested characteristic features of Gorlin syndrome. High-resolution chromosomal bandings of the peripheral blood lymphocytes, polymorphic DNA marker analysis to determine the parental origin of the deletion, array comparative genomic hybridization (CGH) to determine the extent of the chromosomal deletion, and fluorescence in situ hybridization (FISH) to determine the deletion of the PTCH gene were performed. RESULTS: The 850-band level of resolution showed an interstitial deletion of 9q (9q22.3-->q31.3). The parental karyotypes were normal. The karyotype of the proband was 46,XY,del(9)(q22.3q31.3)de novo. Polymorphic DNA marker analysis revealed that the deletion was of paternal origin. Array CGH revealed that the deleted region was about 12 Mb, encompassing the segment from 9q22.32 to 9q31.3. FISH analysis using the BAC probe RP11-34D4 and the probe RP11-43505 indicated the deletion of the PTCH gene. CONCLUSIONS: Fetuses with an interstitial deletion of 9q (9q22.3-->q31.3) may be associated with a low level of MSAFP and a high level of MShCG in the second trimester, and sonographic findings of overgrowth and macrocephaly in the third trimester.

Adult↗

PubMed2002

Perinatal imaging findings of inherited Sotos syndrome.

OBJECTIVES: Although most cases of Sotos syndrome are sporadic, familial cases have been described. In familial cases, the most likely mode of inheritance is autosomal dominant with variable expressivity. We present the perinatal imaging findings of an inherited case. CASE: This was the second pregnancy of a 32-year-old woman with Sotos syndrome. She had given birth to her first child with macrocephaly, ventriculomegaly, macrocisterna magna and neonatal death at 28 weeks' gestation. During this pregnancy, prenatal ultrasonography at 18 weeks' gestation showed only mild dilatation of lateral ventricles. The pregnancy was uneventful until 31 weeks' gestation when fetal macrocephaly, right hydronephrosis, and polyhydramnios began to develop. At 33 weeks' gestation, dilatation of the third ventricle and fetal overgrowth were obvious. At 34 weeks' gestation, macrodolichocephaly, hypoplasia of the corpus callosum, enlargement of the lateral ventricles with prominent occipital horns, and macrocisterna magna were noted. At 36 weeks' gestation, a male baby was delivered with macrodolichocephaly, frontal bossing and a facial gestalt of Sotos syndrome. Birth weight was 3822 g, length 55 cm, and occipitofrontal head circumference 41 cm (all > 97th centile). The magnetic resonance imaging (MRI) scans demonstrated enlargement of the lateral ventricles, the trigones, and the occipital horns, hypoplasia of the corpus callosum, a persistent cavum septum pellucidum and cavum vergae, and macrocisterna magna. CONCLUSIONS: Fetuses at risk for Sotos syndrome may present abnormal sonographic findings of the brain and the skull in association with overgrowth, unilateral hydronephrosis and polyhydramnios in the third trimester. Perinatal MRI studies aid in confirmation of the diagnosis.

Adult↗

PubMed1992

The widened frontal subarachnoid space. A CT comparative study between macrocephalic, microcephalic, and normocephalic infants and children.

The computed tomographic scans of the heads of 67 infants and children with frontal subarachnoid space widening seen during a 5-year period were retrospectively studied. Only 22.3% of patients had macrocephaly. Comparison of the clinical and radiologic characteristics of subarachnoid widening in macrocephalic children and in normocephalic or microcephalic children showed no significant differences. It is concluded that undue emphasis has been laid on the association between this radiologic sign and macrocephaly. Widening of the subarachnoid space in children may be a variation of normal development of brain whereby there is a transient accumulation of cerebrospinal fluid in the frontal region. The term "external hydrocephalus" may therefore be inappropriate in the absence of significant ventricular widening and clinical signs of raised intracranial pressure.

Cephalometry↗

PubMed1985

Dizygotic twins with 3-hydroxy-3-methylglutaric aciduria; unusual presentation, family studies and dietary management.

A 4-month-old infant with hypotonia and macrocephaly was diagnosed as having 3-hydroxy-3-methylglutaric aciduria, using gas chromatography and mass spectrometry and confirmatory enzyme studies. The same diagnosis was made on his asymptomatic non-identical twin. Examination of the pedigree is consistent with an autosomal recessive mode of inheritance. Dietary treatment improved the symptoms of the propositus, but did not prevent episodes similar to Reye's syndrome in both twins. One such episode closely followed immunisation and our experience suggests that children with this disorder should be observed carefully following immunisation. These episodes were accompanied by an overflow of a wide range of abnormal metabolites. Examination of the urine for organic acids should be considered in infants with unexplained hypotonia and macrocephaly, especially if accompanied by abnormal biochemical indices.

Acidosis↗

PubMed1996

MRI findings in children with neurofibromatosis type 1: a prospective study.

To determine the frequency and nature of MRI lesions in children with neurofibromatosis type I (NF1), 50 patients aged 8 to 16 years were evaluated prospectively with cranial MRI. Forty-one children were asymptomatic with respect to central nervous system pathology, and 50% were macrocephalic. Sixteen patients (32%) had normal MRI examinations. Thirty-two patients (64%) had high intensity lesions on T2-weighted images and 16 patients (32%) had hyperintense lesions on T1-weighted images. Seven patients (14%) had ventricular dilatation (associated with increased intracranial pressure in 2) and 11 patients (22%) had optic pathway lesions (optic glioma in 7). MRI was superior to CT in differentiating optic sheath thickening and optic nerve tortuosity from optic glioma in four patients. An intracranial tumour (ependymoma) and sphenoid wing dysplasia were evident in individual patients. Findings previously unreported in NF1 included an aqueductal web resulting in hydrocephalus, intraocular neurofibroma resulting in retinal detachment, and asymptomatic enlargement of the septum pellucidum. T1 and T2 signal abnormalities in isolation were not associated with neurological deficits or the occurrence of macrocephaly, and all lesions that required intervention were suspected clinically. Macrocephaly in the absence of increased intracranial pressure or accelerated head growth is not an indication for neuroimaging in children with NF1. However, the majority of children (68%) had disease-specific abnormalities and thus MRI may provide a useful adjunct to clinical evaluation in the diagnosis of equivocal cases.

Brain↗

PubMed1992

X-linked hydrocephalus: clinical heterogeneity at a single gene locus.

X-linked hydrocephalus-stenosis of the aqueduct of Sylvius sequence (H-SAS, MIM number 30007) is a rare genetic disorder characterized by hydrocephalus, macrocephaly, adducted thumbs, spasticity, agenesis of corpus callosum and mental retardation. We confirm here the localisation of the mutant gene on Xq (Xq 2.8) by linkage analysis in a 5-generation pedigree (maximum lod score of Z = 4.57 at theta = 0.04 with probe St14 at locus DXS52) and emphasise the phenotypic variability of the disease. Ventricular dilatation in affected males was either severe and diagnosed antenatally or moderate and consistent with a long survival with little or no macrocephaly. Since other X-linked syndromes of mental retardation with spasticity and flexion deformities of the thumbs have previously been shown to map to the Xq 2.8 region as well (e.g. MASA syndrome and spastic paraplegia), the present results raise the question of whether H-SAS syndrome, MASA syndrome and spastic paraplegia with mental retardation might represent different phenotypic expression of various mutations at the same locus.

Adult↗

PubMed2001

Clinical approach to the child with a large head.

Majority of children has head size that is appropriate for age and gender. But a few have either too small or too large head at birth or may be of postnatal acceleration. Abnormality of head circumferences is determined by brain size, including any malformations and space occupying lesions, cerebrospinal fluid (CSF) and blood volume, presence of subdural fluid and thickness of skull bones and overlying tissue scalp. Macrocephaly is used when the head size exceeds the mean by more than two standard devotions of age and gender. Macrocephaly is seen in association with several cranioskeletal dysplastic conditions.

Body Height↗