American Journal of Medical Genetics 42:44-50 (1992)
Congenital Hypothalamic Hamartoma Syndrome: Nosological Discussion and Minimum Diagnostic Criteria of a Possibly Familial Form F. Encha-Razavi, J.C. Larroche, J. Roume, G. Migne, AL. Delezoide, M. Gonzales, and N. Mulliez Dipartement d‘Histologie-Embryologie,CHU Henri Mondor (F.E.-R.), Crdteil, U29 INSERM, Hbpital Port Royal (J.C.L.),Unite de Foetopathologia, CHU St-Antoine (J.R., G.M., M.G., N.M.), Hbpital des Enfants Malades, (AL.D.) Paris, France 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 “congenitalhypothalamic hamartoma syndrome” (CHHS).
INTRODUCTION Because of their typical localisation and similar histological structure, hypothalamic hamartomas form a special entity. Most have been reported in infants of 2 years or older in relation with precocious puberty. Recently, a few cases of congenital hypothalamic hamartomas have been reported in newborn infants in a lethal malformation syndrome [Hall et al., 19801. We report on 3 new cases discovered at autopsy in fetuses of 25-40 weeks of gestation. In 2 cases the tumor occurred in association with a skeletal dysplasia only, while in the third case it was part of a malformation syndrome. Based on our clinico-pathologicalfindings and on the review of the literature we discuss the nosology and the minimum diagnostic criteria of a congenital hypothalamic hamartoma syndrome (CHHS). CLINICO-PATHOLOGICAL REPORTS
Family 1 The propositus, born at term after an uneventful pregnancy, was the second child of young, healthy, and unrelated parents. She died a few minutes after birth and was short (45 cm; < 2 SD), had micromelia, short ribs, and cranio-facial and oral abnormalities including macrocephaly, cleft of the upper lip, alveolar frenulae, and short nose. Radiographs showed a skeletal dysplasia comprising short and broad long bones with irregular metaphyses and mild curvature of the radii and ulnae, short and broad phalanges, short and horizontal ribs, narrowing KEY WORDS: skeletal dysplasia, cranio-facervical vertebrae, and hip abnormalities. Chromocia1 abnormalities, skeletal somes were normal. abnormalities, Pallister-Hall An autopsy showed severe pulmonary hypoplasia (11 syndrome g; nl: 49 g 11)with normal lobation and a cleft on the anterior border of the liver. After fixation, the brain weighed 443 g and presented on the basal surface a 15 x 15 mm mass involving the infundibulum (Fig. 1A). The Received for publication September 3, 1990; revision received olfactory tracts were present but the pituitary stalk and March 22, 1991 Address reprint requests to F. Encha-Razavi, M.D., Laboratoire mammillary bodies were absent. There was no report on de Neuropathologie, CHU Henri Mondor, 51, av de Marechal de the sella turcica and pituitary gland. On coronal sections, the tumor involved the hypothalamic region (Fig. Lattre-de-Tassigny, Creteil, 94010, France.
0 1992 Wiley-Liss, Inc.
Congenital Hypothalamic Hamartoma
Fig. 1. Neuropathologicalfindings in patient 1:A:Basal surfaceofthe brain showingthe hypothalamic tumor; B: coronal section of the brain through hypothalamictumor; C:microscopic appearance of the tumor made of neurons of different size and glial cells; cresyl violet. X 750.
Encha-Razavi et al.
ents were healthy and nonconsanguineous. The male fetus had cranio-facial and oral abnormalities with alveolar frenulae, short size (28 cm;