Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form.

We report on congenital hypothalamic hamartomas, discovered at autopsy in 3 unrelated fetuses. In the first 2 patients, the tumor was associated with skeletal dysplasia only. In the third patient, it was part of a non-random congenital malformation association, suggestive of Meckel syndrome. In one family, a previous boy died soon after birth with similar craniofacial and skeletal abnormalities. As far as we know, the association between isolated skeletal dysplasia and congenital hypothalamic hamartomas has not yet been documented in the literature. Nevertheless, a spectrum of skeletal abnormalities has been described in association with congenital hypothalamic "hamartoblastoma" and a constellation of variable visceral malformations under the eponym of "Pallister-Hall syndrome" (PHS). A detailed analysis of the PHS reported cases shows that only skeletal dysplasia and oro-facial abnormalities are present constantly. They show similarities with those found in our first 2 cases. These findings prompt us to consider skeletal dysplasia and oro-facial abnormalities as common denominator and minimum criteria required to define a nosologically distinct, possibly familial entity, which we suggest calling "congenital hypothalamic hamartoma syndrome" (CHHS).     

Further delineation of the epidermal nevus syndrome: Two cases with new findings and literature review

“Epidermal nevus syndrome” (“ENS”) is a neurocutaneous disorder in which epidermal nevi are associated with other abnormalities, most commonly of the skeletal and central nervous systems. We present two cases of epidermal nevus syndrome (ENS) with very different clinical findings. The first case is a newborn with multiple linear epidermal nevi of the trunk and limbs, and several other anomalies, including bony duplications of the lower limbs and hypoplastic left heart syndrome. The second patient, a 6-year-old boy, has a linear nevus sebaceous of the scalp with severe CNS involvement, including generalized seizures, moderate mental retardation, microcephaly, and a left hemiparesis. He also has genitourinary, cardiac, and skeletal defects. These two patients exhibit several abnormalities not previously recognized and illustrate the wide clinical spectrum of “epidermal nevus syndrome.” We present a review of the clinical findings in 74 cases of “ENS.” Correlation was noted between the presence of skin lesions located on the head and CNS involvement. The wide clinical spectrum of “ENS” as illustrated by these two patients suggests that “ENS” is a causally heterogeneous group of disorders. © 1993 Wiley-Liss, Inc.     

Skeletal dysplasias with gracile bones: Three new cases,including two offspring of a mother with a dwarfing condition

We describe 3 new cases of a rare form of dwarfism (so-called “lethal skeletal dysplasia with gracile bones” or “osteocraniostenosis”), a condition characterized by thin, brittle bones and death in late gestation or early neonatal life. The first was a 37-week gestation female who died at delivery. She had facial anomalies and positional abnormalities of the hands and feet. The others were male stillborn sibs, who died in utero in the third trimester. Their mother had an undiagnosed dwarfing condition associated with body asymmetry, microcephaly, and unusual facial appearance. Both fetuses were documented by ultrasound to have short limbs and probable long bone fractures late in the second trimester. At autopsy, one fetus had no spleen and the other a hypoplastic spleen. Radiographically, all three cases had very thin diaphyses, diaphyseal fractures, and thin ribs and clavicles. In contrast to the first case who had a normally mineralized calvaria, the sibs had grossly deficient calvarial mineralization. Microscopically, endochondral ossification was qualitatively normal but quantitatively deficient in all three cases. The long bones, especially those of the sibs, lacked the well-defined outer cortex in the mid-shaft normally seen by the third trimester. This failure of organization into the cortex and medulla suggests a failure of bone remodelling. Given the variable presentation in these cases, “lethal skeletal dysplasia with gracile bones” is probably a heterogeneous disorder. The recurrence in one family suggests that the mother has somatic/germline mosaicism of a lethal gene, expressed clinically as growth failure and asymmetry. Am. J. Med. Genet. 76:125–132, 1998. © 1998 Wiley-Liss, Inc.     

Non-cardiac malformations in individuals with outflow tract defects of the heart: The Baltimore-Washington infant study (1981–1989)

In the Baltimore-Washington Infant Study, a regional case-control study of 4,390 liveborn infants with cardiovascular malformations (CVM), 642 patients (14.2%) had outflow tract abnormalities, with extracardiac defects in 157 (～25%) of them. Associated defects were found in 1/3 of patients with normal great arteries, but only in 1/10 of patients with transposition of great arteries (TGA). The extracardiac defects were especially rare in the groups “TGA with intact ventricular septum” and “TGA with ventricular septal defect.” Patients with multiple associated defects outnumbered patients with isolated associated defects in the ratio 2.5:1. The associated defects were heterogeneous: 46 patients had chromosome abnormalities, 16 had different Mendelian syndromes, and 36 had associations (DiGeorge sequence and VACTERL association were the most frequent). A new syndrome of multiple congenital abnormalities including tetralogy of Fallot, and rare cases of chromosomal and Mendelian syndromes (distal trisomy 1q, tetrasomy 8p, Holzgreve syndrome) are described briefly. Sufficient variability of a spectrum of conotruncal defects in the patients with the same chromosomal or Mendelian syndromes suggests that at least in some cases different conotruncal defects are stages of the same morphologic spectrum. The analysis of conotruncal defects in sibs of patients with Mendelian syndromes may provide new data about the links between different definitive forms of CVM. © 1995 Wiley-Liss, Inc.     

Spondyloperipheral dysplasia

We present a patient with spondyloperipheral dysplasia, a rare skeletal dysplasia which is characterized by vertebral body abnormalities (platyspondyly, end-plate indentations) and brachydactyly. Our patient also manifested a characteristic “pugilistic” face, sensorineural deafness and mental retardation. This chondroosseous dysplasia appears to be inherited as an autosomal dominant disorder. It appears that there is considerable clinical variability in spondyloperipheral dysplasia. © 1995 Wiley-Liss, Inc.     

Branchial cyst,sensorineural deafness,congenital heart defect,and skeletal abnormalities: Branchio‐oto‐cardio‐skeletal (BOCS) syndrome?

This article describes a boy with an unusual combination of features, namely, intrauterine growth retardation, short stature, branchial cyst, sensorineural hearing loss, congenital heart defect, rib and vertebral abnormalities, micromelia, brachymesophalangia, and absence of phalanges. We suggest that these findings comprise a new entity of combined branchio‐oto and cardio‐digital developmental field abnormalities, which we termed branchio‐oto‐cardio‐skeletal syndrome. The pattern of inheritance remains uncertain. © 2002 Wiley‐Liss, Inc.     

Exclusion of candidate loci and cholesterol biosynthetic abnormalities in familial Pallister-Hall syndrome.

Pallister-Hall syndrome (PHS) was originally described in 1980 in six sporadic cases of children with structural anomalies including hypothalamic hamartoma, polydactyly, imperforate anus, and renal and pulmonary anomalies. In 1993, the first familial cases were reported, including affected sibs and vertical transmission. Three of these families are sufficiently large to allow initial evaluation by linkage studies to candidate genes or loci. We have evaluated candidate loci for PHS based on three clinical observations. The first is a patient with PHS-like malformations, including a hypothalamic hamartoma, and an unbalanced translocation involving 7q and 3p. The second is a family with familial PHS where the founder's father had an autosomal dominant hand malformation previously mapped to 17q. The third is the phenotypic overlap of PHS and Smith-Lemli-Opitz syndrome. In this report, we exclude these loci as candidates for linkage to the PHS phenotype on the basis of lod scores of less than-2.0. We conclude that hypothalamic hamartoma is not specific to PHS and that the dominant hand malformation in one of the families was a coincidence. To evaluate the relationship of PHS to Smith-Lemli-Opitz syndrome, we analysed levels of cholesterol and intermediate metabolites of the later stages of cholesterol biosynthesis. There is no evidence of a generalised disorder of cholesterol biosynthesis in patients with familial PHS. On genetic and biochemical grounds, we conclude that PHS and Smith-Lemli-Opitz syndrome are not allelic variants of a single locus.     

Satoyoshi syndrome: An unusual postnatal multisystemic disorder

Satoyoshi syndrome is a rare disorder of unknown cause characterized by progressive, painful intermittent muscle spasms, malabsorption, alopecia, amenorrhea, and skeletal abnormalities mimicking a skeletal dysplasia. We describe a 19-year-old Caucasian woman with characteristic manifestations starting at age 9. The report of this patient confirms that this condition is not limited to the Asian population. © 1995 Wiley-Liss, Inc.     

Gracile bone dysplasia

Gracile bones are a frequent abnormality associated with fetal hypokinesia of any cause. With the exception of thin, undermineralized bones, the chondro-osseous structure is usually normal in these cases. We present a lethal skeletal dysplasia comprising minor anomalies, central nervous system abnormalities, gracile long bones, and abnormal chondro-osseous morphology. In addition to a short, disordered growth plate, the chondrocytes contained dilated loops of rough endoplasmic reticulum, suggesting an abnormality of an extracellular matrix protein. This protein appears to have effects on chondro-osseous and on facial and central nervous system development. We suggest the term “gracile bone dysplasia” to describe this disorder. Am. J. Med. Genet. 75:95–100, 1998. © 1998 Wiley-Liss, Inc.     

The Wolf-Hirschhorn syndrome

Most cases of Wolf-Hirschhorn syndrome occurring among children who die during the perinatal period are not diagnosed by morphologists. However, analysis of the morphological data on the Wolf-Hirschhorn syndrome reveals that association of typical external features and abnormalities of the brain (shortening of the H2 area of Ammon's horn, dystopic dysplastic gyrae in the cerebellum), eyes (colobomata, microphthalmos, retinal dysplasia) and kidneys (bilateral or unilateral agenesis, cystic dysplasia or polycystosis) with diaphragmatic hernia allows the establishment of a diagnosis of the syndrome without cytogenetic investigation.     

Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome)

We report one new case of congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome) and one case of a diencephalic nodule associated with craniofacial malformations. Based on a review of 11 cases of Pallister-Hall syndrome documented by pathological examination, two cases presumed by phenotype, three cases of hypothalamic hamartoma with craniofacial anomalies only, and several cases of related interest, we delineate the clinical, neuroradiologic, and neuropathologic manifestations which aid in differential diagnosis. Clinical manifestations in infants with Pallister-Hall syndrome included postaxial polydactyly with nail dysplasia, short nose with flat nasal bridge, apparently low-set, posteriorly angulated ears, kidney and lung anomalies, congenital heart defects, imperforate anus, and micropenis with undescended or hypoplastic testes in males. These manifestations were associated with varying degrees of panhypopituitarism and pituitary aplasia. In three cases of hypothalamic hamartoma associated with craniofacial anomalies only, the face resembled that of holoprosencephaly. Other cases of hypothalamic hamartoma have had associated palate or heart defects or presented with precocious puberty. Of the infants with a hypothalamic hamartoblastoma at autopsy, neuropathologic findings were consistent with a primitive neuroectodermal tumor. Surgical tissue from our sole survivor suggested such tumors might mature, and the tumor has not recurred. Neuroradiologic diagnosis may be difficult but should be attempted in infants with these clinical manifestations; due to the need for prompt initiation of appropriate therapy.     

Simpson-Golabi-Behmel syndrome: Congenital diaphragmatic hernia and radiologic findings in two patients and follow-up of a previously reported case

This report suggests the association of congenital diaphragmatic hernia in Simpson-Golabi-Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half-nephew of our previously reported 8-year-old boy with this syndrome. Review of the skeletal roentgenograms of these 2 affected males, and those of the previously reported 8-year-old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn (“advanced bone age”). We also report the follow-up of the 8-year-old boy, now 16 years old, who continues to have significant overgrowth and speech, dental, developmental, and adjustment problems. © 1993 Wiley-Liss, Inc.     

Extended survival in a new case of ter Haar syndrome: Further delineation of the syndrome

We present a boy followed from age 5–13 years who is the fifth reported case of ter Haar syndrome. This is a recently-named entity comprising congenital glaucoma, hypertelorism, congenital heart defects and kyphoscoliosis, skeletal dysplasia, and developmental delay. These patients were originally thought to have an autosomal-recessive form of Melnick-Needles syndrome, and were only identified as having a distinct syndrome with the report of the fourth case. Probable autosomal-recessive inheritance is based on consanguinity in 4 of 5 cases. Ocular, cardiac, and craniofacial findings distinguish ter Haar syndrome as a distinct entity. Our patient is the longest survivor at present, suggesting that there is heterogeneity in this syndrome or, alternatively, that aggressive therapy of the congenital heart defects has significant effect. Am. J. Med. Genet. 70:267–272, 1997. © 1997 Wiley-Liss, Inc.     

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): Presentation in two unrelated patients in the United States

This is a report of two North American patients with spondyloepimetaphyseal dysplasia with joint laxity, an uncommon autosomal recessive skeletal dysplasia rarely reported outside of South Africa. Patients with SEMDJL have vertebral abnormalities and ligamentous laxity that results in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubbed feet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed. Diagnosis in infancy may be difficult because many of the typical findings are not apparent early and only evolve over time. We review the physical and radiographic findings in two unrelated patients with this disorder in order to increase the awareness of this disorder, particularly for clinicians outside of South Africa. Am. J. Med. Genet. 86:245–252, 1999. © 1999 Wiley-Liss, Inc.     

Thyroid dysgenesis and the dysplasia hypothesis in tuberous sclerosis

Thyroid dysfunction is rare in tuberous sclerosis, although papillary adenomas (hamartomas) of the thyroid gland have been reported in a few autopsy cases. We describe a child with tuberous sclrosis and primary congenital hypothyroidism secondary to a dysgenetic thyroid gland. To our knowledge, this association has not been reported previously. Although the association of these two disorders in one patient may be merely coincidence, we speculate that the dysgenetic thyroid gland in this patient may represent a “hamartia” as a consequence of the tuberous sclerosis gene. © 1993 Wiley-Liss, Inc.     

Possibly new multiple congenital anomaly syndrome: Cranio-fronto-nasal dysplasia with Poland anomaly

We present a possibly new multiple congenital anomaly syndrome of craniosynostosis, Poland anomaly, cranio-fronto-nasal “dysplasia,” and genital and breast anomalies. A similar pattern of anomalies was observed in two previous cases from the literature; however, some peculiar findings suggest that these cases might represent a new multiple congenital anomaly syndrome. © 1996 Wiley-Liss, Inc.     

Asymptomatic laryngeal malformations are common in patients with Pallister‐Hall syndrome

Pallister‐Hall syndrome (PHS) comprises hypothalamic hamartoma, polydactyly, pituitary dysfunction, laryngotracheal cleft, imperforate anus, and other anomalies. Some patients with PHS have a bifid epiglottis, a rare malformation. Greig cephalopolysyndactyly syndrome (GCPS) comprises polydactyly with craniofacial malformations without the PHS malformations. Both disorders are caused by mutations in the GLI3 gene. Laryngoscopy on 26 subjects with PHS showed that 15 had a bifid or cleft epiglottis (58%) and none of 14 subjects with GCPS had a cleft epiglottis. The malformed epiglottis was asymptomatic in all of the prospectively evaluated subjects. One additional PHS subject was found to have bifid epiglottis and a posterior laryngeal cleft on autopsy. We conclude that bifid epiglottis is common in PHS but not GCPS. Posterior laryngeal clefts are an uncommon manifestation of PHS and are identified only in severely affected patients. The diagnosis of a bifid epiglottis should prompt a thorough search for other sometimes asymptomatic anomalies of PHS to provide better medical care and recurrence risk assessment for affected individuals and families. Am. J. Med. Genet. 94:64–67, 2000. Published 2000 Wiley‐Liss, Inc.