Hypothalamic Hamartoblastoma Research Articles

Pallister\u2013Hall syndrome with orofacial narrowing and tethered cord: a case report

BackgroundPallister–Hall syndrome is a rare, autosomal dominant, genetic disorder characterized by different congenital abnormalities: hypothalamic hamartoblastoma, bifid or shortened epiglottis, polydactyly, renal anomalies, and imperforate anus.Case presentationIn this case report, we describe the case of a 13-year-old Lebanese-Armenian boy born with Pallister–Hall syndrome showing newly associated manifestations (orofacial narrowing and tethered cord), and currently showing a spontaneous puberty with normal growth pattern following management with growth hormones.ConclusionsThis case report shows a practical approach to this very rare syndrome, mainly with testosterone and growth hormones, and its follow-up in the long term. Being familiar with such cases may allow improvement of our knowledge for better management in the future.

The early history of Pallister–Hall syndrome—Buried treasure of a sort

Pallister–Hall syndrome was initially recognized under fairly unique circumstances involving exhumation of the very first case. The first two cases had dramatic and unusual features including a hypothalamic hamartoblastoma, imperforate anus, an unusual type of polydactyly with the extra digit being central, hypopituitarism with secondary hypoadrenalism, and lethality after birth (probably due to hypoadrenalism). Within a short time frame, four additional cases were identified. As the full spectrum and variability of anomalies was recognized, it became clear that it was not such a rare disorder. Shortly after familial cases were recognized, the responsible gene was identified at GLI3. However, since other different conditions also involved GLI3, elaborating the domains of the gene and the types of mutations needed to be defined in order to have a clear correlation of the genotype–phenotype relations.

Neonatal hypothalamic hamartoma: a differentiating nonlethal hamartoblastoma

The authors report on a patient with a large hypothalamic hamartoma with a cleft lip and palate and seizures. Neuroimaging revealed a large extraaxial, intradural mass in the prepontine and interpeduncular cisterns with significant distortion of the brainstem. A stereotactic transfontanel needle biopsy revealed a cellular lesion that contained immature-appearing neuroepithelial cells consistent with prior descriptions of hypothalamic hamartoblastoma. While having a low level of proliferation by Ki67 (MIB-1) labeling, the lesion also contained evidence of neuronal maturation, with many cells expressing neuronal nuclear antigen as observed during immunohistochemical analysis. Further clinical evaluation revealed no other significant congenital abnormalities, and the patient was discharged home. Outpatient follow up has continued for 2 years and the patient has been doing well, requiring no further treatment. This case illustrates that, despite its immature and proliferative histological appearance, this rare neonatal mass can be regarded as a "differentiating" hypothalamic hamartoma and can have a favorable prognosis.

An Infant Case of Pallister-Hall Syndrome Treated with Hormone Replacement.

Pallister-Hall syndrome was first described by Hall et al. in 1980. This syndrome is characterized by hypothalamic hamartoblastoma, hypopituitarism, polydactyly, imperforate anus and other anomalies. We report a case of a male infant with hypothalamic tumor, hypopituitarism, dysplastic metacarpals, micropenis and remarkable hypoglycemia. He has been treated with hydrocortisone, thyroid hormone, NaCl, fludrocortisone acetate and GH. He has grown well on this therapy.

The extreme Spectrum of Pallister-Hall syndrome

Pallister-Hall syndrome can result from GLI 3 gene mutation and is characterized by hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly. It has a wide spectrum of severity, from perinatal lethal to minimally symptomatic. Familial cases with different expressiveness were reported before. We herein report a 22-week terminated fetus, which was a product of a GIPO 16-year-old healthy mother. Initial ultrasound at 20 weeks gestation revealed severe oligohydramnios and a small fetus. Subsequent ultrasound revealed absent stomach, dysplastic kidneys, short limbs, distal dysplasia, abnormal facies and the possibility of Roberts syndrome was discussed. The patient was counseled and pregnancy termination was sought. Cytogenetic studies revealed a normal 46,XY male karyotype and negative study for centromere analysis. Autopsy revealed a normally grown 22-23 week male fetus with hypothalamic hamartoma, polydactyly, imperforate anus and multiple other congenital anomalies. He had small, wide-spaced eyes, bilateral choanal atresia, soft tissue mass of the philtrum, small mouth with soft tissue fusion between alveolar ridges, lips and tongue, abnormal palate with possible midline clefting, micrognathia and simple lowset ears. There were short upper extremity digits with hypoplastic nail bed and bilateral partial duplication and fusion of the fourth digits. The feel were markedly everted with small medially placed great toes. The third, fourth and fifth digits are all short with poor nail bed. All digits had prominent syndactyly. There was anal atresia with blind rectosigmoid colon emptying into the bladder region without rectovesicular fistula. There was bilateral renal hypoplastic dysplasia with disorganization of the cortex. Brain examination revealed hypothalamic hamartoblastoma, 1.0 × 1.5 × 1.0 cm. There was absent cerebellar vermis, absent corpus callosum, probable absent olfactory grooves and tracts and sella turica wilh no pituitary gland present. Small adrenal glands with disorganization of the adrenal cortex were also noted. Cardiac exam revealed malrotation of the great vessels and cardiomegaly. Pulmonary hypoplasia and oligohydramnios sequence was noted with flexion conlractures of the joints. Our patient represents an extreme spectrum of PHS and emphasizes the importance of recognition of fetal syndrome and documented autopsy for genetic counseling.

Bifid Epiglottis

The true bifid epiglottis is a rare congenital anomaly typically discovered during the evaluation of stridor in an infant or newborn. While it is not classified as a specific syndrome, there are frequent associations of other congenital anomalies with the bifid epiglottis. These include midline defects (such as microphallus, hypospadius, imperforate anus, and midline laryngeal cleft), endocrine disorders (including congenital hypopituitarism), and central nervous system neoplasms, including hypothalamic hamartoblastoma. The embryogenesis and options for surgical management of this anomaly are reviewed, and one case is presented in detail.

Imperforate anus, bilateral hydronephrosis, bilateral undescended testes and pituitary hypoplasia: a variant of Hall‐Pallister syndrome or a new syndrome?

A patient with multiple congenital malformations, including imperforate anus, bilateral cryptorchidism and microphallus, is described. At 4 months of age the infant had generalized convulsions and hypoglycaemia. Bilateral hydronephrosis was diagnosed at 8 months of age. At 10 months he was diagnosed as having panhypopituitarism secondary to anterior pituitary hypoplasia, shown on CT and MRI scans. This clinical picture partially resembles that of Hall-Pallister syndrome. However, the absence of some typical features such as craniofacial and limb abnormalities and, above all, hypothalamic hamartoblastoma, would also suggest the possibility of a new, previously unreported, syndrome.

Numerical syndromology: A mathematical approach to the nosology of complex phenotypes

Numerical taxonomy is defined by Sneath and Sokal as the grouping of taxonomic units on the basis of their character states by numerical methods of multivariate data analysis, and syndromology as the study of multiple congenital anomaly (MCA) syndromes and of their nosology. We present here an application of those methods to the analysis of overlapping syndromes. The main advantage of numerical taxonomy is that it allows simultaneous objective and unweighted analysis of multiple traits, giving the possibility to test mathematically the clinical hypotheses about the heterogeneity between closely resembling syndromes and uncovering objective patterns of anomalies, to be compared with the subjective pattern recognition process which characterizes most of the diagnostic approach in syndromology. In this paper, we explored 5 syndromes whose most severe expression belongs to the cerebroacrovisceral early lethality (CAVE) phenotype: hydrolethalus, severe Smith-Lemli-Opitz, orofaciodigital type VI (Varadi-Papp), holoprosencephaly-polydactyly, and Pallister-Hall syndromes. Fifty-five published cases, including many overlapping cases, were submitted to principal factor analysis followed by hierarchical clustering and graphical scaling. Results show that the 5 syndromes clearly constitute independent phenotypic entities, that some of the original diagnoses have to be reconsidered, and that many of the overlapping cases may be unambiguously set in one category. Hypothalamic hamartoblastoma appears to be a nonspecific dysplasia occurring in any of the 5 disorders.

Syndromal hypothalamic hamartoblastoma with holoprosencecephaly sequence, microphthalmia, pulmonary malformation, radial hypoplasia and M??llerian regression

A 24-week-old fetus is described here with holoprosencephaly sequence (arhinencphaly and agensis of the corpus callosum) associated with brain and meningeal dysplasia, microphthalmia with an ectopic pigementary layer, hypothalamic hamartoblastoma, preaxial asymmetric limb reduction, lung hypoplasia, gastric hypoplasia, Müllerian regression, intestinal malrotation, asplenia and normal chromosomes. The differential diagnosis includes the Cerebroacrovisceral-Early Lethality (CAVE) phenotype, and the Pallister-Hall syndrome, but the anomalies best fit the severe form of microgastira-limb reduction syndrome. Together with a previous case reported by Meinecke, the pattern of anomalies appears to represent a combination of defects, related to but distinct from the microgastira-limb reduction syndrome.

Variability versus heterogeneity in syndromal hypothalamic hamartoblastoma and related disorders: Review and delineation of the Cerebro‐Acro‐Visceral Early lethality (CAVE) multiplex syndrome

We report on a case of neonatal hypothalamic hamartoblastoma with holoprosencephaly, Hirschsprung disease, and tetramelic postaxial polydactyly. Twenty-seven previous cases of congenital hypothalamic embryonic tumours with associated congenital defects are reviewed. A classification in isolated, associated, and syndromal forms is proposed. The difficulties encountered in differential diagnosis between the syndromal form (mainly represented by the Pallister-Hall syndrome) and related diseases as Smith-Lemli-Opitz type II, holoprosencephaly-polydactyly, orofaciodigital type VI and hydrolethalus syndromes are outlined. Two pathogenic mechanisms are discussed: a classical pleiotropic model and single sequence model. The latter is sufficient to delineate syndromal hypothalamic hamartoblastoma. With the former, syndromal hypothalamic hamartoblastoma cannot be clearly recognized in the absence of a CNS tumour, a child with syndromal hypothalamic hamartoblastoma cannot be reliably diagnosed as Pallister-Hall rather than another MCA syndrome, and, ultimately, the existence of Pallister-Hall syndrome could be questioned, as it could only be the extreme expression of one or several other syndromes. As this hypothesis cannot be proven or disproven at this point, the authors suggest creating the concept of multiplex phenotype. "Cerebro-Acro-Visceral Early lethality multiplex syndrome" is suggested to encompass all the ambiguous cases. Within this complex, an operative classification key is proposed.

Pallister‐Hall syndrome associated with an unbalanced chromosome translocation

We report 3 cases of Pallister-Hall syndrome involving hypothalamic hamartoblastoma, hypopituitarism, cranial, and limb abnormalities. The first 2 cases represent the first apparent sibs reported with this syndrome. Patient 1 represents the first known patient with this syndrome with an abnormal karyotype.

Extending the Pallister‐Hall syndrome to include other central nervous system malformations

Hall-Pallister syndrome is defined by specific facial anomalies, post axial polydactyly, imperforate anus, and brain anomalies including a rare diencephalic mass, hypothalamic hamartoblastoma. In this article, two patients are described with the usual features of Hall-Pallister syndrome, including diencephalic anomalies, but without hamartoblastomas. These patients may suggest an appropriate extension of the definition of the Hall-Pallister syndrome.

1287 SYNDROMES ASSOCIATED WITH POLYDACTYLY AND HYPOPITUITARISM

We report two female infants with postaxial polydactyly and hypopituitarism of differing etiologies. The first infant was born at term to a 26-year-old gravida 6 para 2 abortus 4 woman who noted markedly decreased fetal movement and intrauterine growth retardation. She was delivered from a breech presentation with posteriorly rotated simplified auricles, short nose, flat nasal bridge, microglossia, micrognathia, cleft posterior palate, short limbs with dislocated hips, postaxial polydactyly of hands and feet, bilateral simian creases, and 2-3 syndactyly of the toes. She died at 21 hours of age and autopsy revealed hypothalamic hamartoblastoma, bilateral hypoplastic renal ectopia, bilateral pulmonary hypoplasia, and a bifid epiglottis. Family history revealed that the mother's sister had died at 17 hours of age with remarkably similar dysmorphic features (no autopsy done), and this is the first report of apparent familial recurrence for Hall-Pallister syndrome. The second infant was born by cesarean section at 42 weeks with postaxial polydactyly of the left hand and primary panhypopituitarism. This pregnancy in a 21-year-old gravida 2, abortus 1 woman was complicated by extremely low maternal estriols. Size at birth and a cranial CT scan were normal, and the family history was negative for other individuals with hypopituitarism or polydactyly. Postaxial polydactyly may be associated with hypopituitarism, especially when associated with cleft palate, choanal atresia, congenital heart disease, and basal brain anomalies.

Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus, and postaxial polydactyly--a new syndrome? Part II: Neuropathological considerations.

Unusual and virtually identical hypothalamic tumors were recently studied in three unrelated neonates with a similar complex malformation syndrome. Previous reports of either the hypothalamic tumors or the syndrome as a whole have not been found. Each tumor was apparent on the inferior surface of the cerebrum and extended from the optic chiasma to the interpeduncular fossa. The tumor replaced the hypothalamus and other nuclei which originate in the embryonic hypothalamic plate; it was principally composed of cells resembling primitive, undifferentiated germinal cells. The term "hamartoblastoma" is used to designate these tumors in order to emphasize the malformational and neoplastic aspects. In addition, short olfactory tracts suggest a relation to the arrhinencephaly field defect.