Holoprosencephaly-diencephalic hamartoblastoma (HDH).

2007-09-01   Marco Castori , Paola Grammatico 

Medical Genetics, Institute of Experimental Medicine, Università La Sapienza, San Camillo-Forlanini Hospital, Rome, Italy

Identity

Name

Holoprosencephaly-diencephalic hamartoblastoma (HDH).

Alias

Holoprosencephaly-diencephalic hamartoblastoma association, Holoprosencephaly-hypothalamic hamartoblastoma, Holoprosencephaly-diencephalic hamartoma

Note

HDH is an extremely rare developmental field defect primarily involving the prosencephalon. The most accredited hypothesis is that the hypothalamic hamartoma formation, which occurs early in embryogenesis, produces a cascading process of subsequent craniofacial defects including holoprosencephaly, microphthalmia, hemifacial microsomia, neuronal migration defects, and brainstem\/posterior fossa and meningeal anomalies.

Inheritance

The inheritance pattern of HDH is still obscure and probably heterogeneous. Environmental\/stochastic causes may also contribute for a significant proportion of cases.

Omim

-

Mesh

D054975

Orphanet

672 Pallister-Hall syndrome

Umls

C0265220

Clinics

Phenotype and clinics

HDH equally affects males and females. Nearly 100% of the patients present some features of holoprosencephaly. The spectrum of these anomalies is wide, ranging from alobar holoprosencephaly to microforms, such as isolated single central medial incisive, or cleft palate. The most consistent holoprosencephalic features are hypo\/aplasia of the corpus callosum, arhinencephaly and premaxillary agenesis. Unilateral or bilateral microphathalmia and neuronal migration\/cortical anomalies are quite common abnormalities. Additional findings include meningeal abnormalities, such as cysts and dysplasia, and brainstem and posterior fossa malformations. The first and second branchial arches derivatives may also be asymmetrically affected leading to a significant clinical overlap with the oculo-auriculo-vertebral spectrum. Fifty to sixty per cent of the patients also show extracephalic features, with an excess of midline and laterality determination abnormalities, thus configuring a polytopic developmental field defect. The axial skeleton is the most commonly involved structure, while heart, kidneys, gastrointestinal tract, genitourinary system and limbs are more rarely affected.

Neoplastic risk

On embryological perspective, hypothalamic hamartoma\/hamartoblastoma is a malformation, not a true tumor. Other benign growth lesions, including meningeal angiomatosis, frontal lipoma, tongue cyst, epignathus and gum nodules, have been observed in about 20% of the cases. However, no increased risk of malignancies has been reported in HDH patients.

Treatment

In those patients who survive (see below), the treatment is usually conservative and symptomatic. Surgical repair could be requested for specific potentially life-treating or disfiguring malformations, such as cleft palate, congenital heart disease and genital anomalies. Invasive treatment of hypothalamic hamartomas is usually requested only in presence of intractable seizures. In this case, the experience is limited to non syndromic hamartomas and therapeutic options include surgical resection by conventional craniotomy, microsurgical technique via transcallosal approach and stereotactic radiofrequency thermocoagulation.

Prognosis

HDH usually has a poor prognosis and is lethal in about 50% of the cases. Mental retardation, epilepsy and precocious puberty are quite common complications (50-60%) in the surviving patients.

Cytogenetics

Note

In one case a 7q36 terminal deletion was demonstrated, while another patient showed a 69, XXX triploid karyotype. Therefore, although rarely positive, standard karyotype and subtelomeric rearrangement analysis are recommended in all HDH patients.

Genes involved and Proteins

Note

Although mutations of this gene have not yet been identified in HDH, a terminal 7q deletion has been documented in one patient and an additional case, showing single central medial incisive and hypophyseal hamartoma, has been described with SHH heterozygous mutation. These evidences suggest that SHH is a potential candidate-gene for those HDH cases who still lack a known cause (e.g. chromosome imbalance or teratogenic exposure).

Note

A single patient showing a SOX2 heterozygous mutation and presenting with hypothalamic hamartoma, unilateral microphthalmia, hypoplastic anterior hypophysis and corpus callosum has been described. Although the observed phenotype cannot be unambiguously interpreted as an atypical form of holoprosencephaly, future studies are expected to demonstrate a causal relationship between SOX2 mutations and HDH.

Bibliography

Pubmed IDLast YearTitleAuthors
119520802002Gelastic seizure with tectal tumor, lobar holoprosencephaly, and subependymal nodules: clinical report.Akman CI et al
96619691998Gelastic epilepsy, hypothalamic hamartoma, precocious puberty, and agenesis of the corpus callosum: a new association.Alikchanov AA et al
32967551987Hydrolethalus (Salonen-Herva-Norio) syndrome: further clinicopathological delineation.Anyane-Yeboa K et al
172304852007Reassessment of holoprosencephaly-diencephalic hamartoblastoma (HDH) association.Castori M et al
174977222007A triploid fetus further expands etiological heterogeneity in holoprosencephaly-diencephalic hamartoblastoma.Castori M et al
13083641992Congenital hypothalamic hamartoma syndrome: nosological discussion and minimum diagnostic criteria of a possibly familial form.Encha-Razavi F et al
137057781960Meningeal angiomatosis, arhinencephaly, agenesis of the corpus callosum and large hamartoma of the brain, with neoplasia, in an infant having bilateral nasal proboscis.GITLIN G et al
124536042002Hypothalamic hamartoma, gelastic epilepsy, precocious puberty--a diffuse cerebral dysgenesis.Gulati S et al
72119521980Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly--a new syndrome? Part I: clinical, causal, and pathogenetic considerations.Hall JG et al
31462991986Congenital hypothalamic hamartoma associated with severe midline defect: a developmental field defect. Report of a case.Hennekam RC et al
176439652007Stereotactic radiofrequency thermocoagulation for hypothalamic hamartoma with intractable gelastic seizures.Homma J et al
26884161989Case report and delineation of the congenital hypothalamic hamartoblastoma syndrome (Pallister-Hall syndrome).Iafolla K et al
169328092006Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.Kelberman D et al
156617032005Hypothalamic hamartoma associated with a craniopharyngeal canal.Kizilkilic O et al
16052681992Pallister-Hall syndrome associated with an unbalanced chromosome translocation.Kuller JA et al
130852731953Hamartoma of the hypothalamus; report of two cases with associated developmental defects.MARCUSE PM et al
144388991959Bilateral nasal proboscis associated with unilateral anophthalmia, unilateral diffuse pigmentation of the conjunctiva, and anomalies of the skull and brain.ROSEN Z et al
159429532005Single median maxillary central incisor, hypophyseal tumor, and SHH mutation.Ribeiro LA et al
108678032000Diencephalic neuronal hamartoma associated with congenital obstructive hydrocephalus, anophthalmia, cleft lip and palate and severe mental retardation: a possible new syndrome.Rossiter JP et al
84270751993Duplication of the pituitary gland as shown by MR.Ryals BD et al
162380842005Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma.Saxonhouse MA et al
106708952000Epignathus teratoma: report of three cases with a review of the literature.Vandenhaute B et al
16217561992Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: review and delineation of the cerebro-acro-visceral early lethality (CAVE) multiplex syndrome.Verloes A et al
77355031995Syndromal hypothalamic hamartoblastoma with holoprosencephaly sequence, microphthalmia, pulmonary malformations, radial hypoplasia and müllerian regression: further delineation of a new syndrome?Verloes A et al
71431761982Solitary central maxillary incisor associated with precocious puberty and hypothalamic hamartoma.Winter WE et al

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