Hypothalamo-pituitary hormone insufficiency associated with cleft lip and palate

Two male patients with congenital cleft lip and palate first seen at ages 10.2 and 21.5 years presented with typical signs of hypothalamic-interior pituitary hormone deficiencies. They were found to lack GH, LH, and FSH and to be partially deficient in TSH and ACTH. Several congenital defects may explain this rare syndrome affecting midline structures in the proximity of the maldeveloped palate, including Rathke's pouch, which migrates distally to develop into the anterior pituitary.     

Septo-optic dysplasia and growth hormone deficiency. De Morsier-syndrome (author's transl)

In a 4 1/2 year old blind boy with cryptorchidism and severe growth retardation a deficiency of growth hormone was verified. He has the symptoms of septo-optic dysplasia, an inborn malformation of the brain with hypoplasia of the optic nerves and tractus opticus, absent septum pellucidum and variable pituitary hormone deficiencies. Treatment with growth hormone was successful. In children with growth hormone deficiency the syndrome seems to be not infrequent.     

Pituitary dysfunction, morbidity and mortality with congenital midline malformation of the cerebrum

The purpose of this study was to review systematically a series of patients with congenital midline brain defects and pituitary dysfunction in early childhood and to quantitate the degree of dysfunction and clinical outcome. This study was a retrospective analysis of case notes of patients with pituitary dysfunction associated with either a midline cerebral anomaly and/or optic nerve hypoplasia. Forty patients were studied: 2 with semilobar holoprosencephaly, 2 with lobar holoprosencephaly, 18 with septo-optic dysplasia with an intact septum pellucidum, 7 with septo-optic dysplasia with an absent septum pellucidum, 7 with agenesis of the corpus callosum and 4 patients with isolated pituitary hypoplasia. An early age of diagnosis, feeding difficulties, neurodevelopmental disability, visual impairment and seizures were common occurrences. Despite disordered neuro-anatomy, most seizure disorders were caused by hypoglycaemia or hypernatraemia. Hypotensive/hypoglycaemic crises accounted for two out of three deaths within the study population. Most of patients had multiple pituitary hormone deficiency with growth hormone and Adreo corticotrophic hormone deficiency occurring most commonly. Unequivocal isolated hypothalamic dysfunction was an uncommon finding. In congenital midline brain malformation there is a spectrum of disordered neuro-anatomy associated with variable pituitary dysfunction. Clinical manifestations such as convulsions and developmental delay may be due to disordered metabolism and/or neuro-anatomy. Conclusion Children with congenital midline brain defects frequently manifest convulsions, neurodevelopmental disability and poor growth due to disordered metabolism and/or neuro-anatomy. Treating clinicians must be aware of the complex, dynamic neurological and metabolic nature of these patients and their potential for early demise. Received: 9 February 1998 / Accepted in revised form: 29 July 1998     

Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation

Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient’s mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.     

Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum

The clinical and endocrinological findings in 24 children with septo-optic dysplasia and/or agenesis of the corpus callosum are described with particular reference to posterior pituitary function. Nine had diabetes insipidus. The prevalence of diabetes insipidus was similar in children with complete and incomplete forms of septo-optic dysplasia. Maintenance of normal osmotic balance was very difficult in six of these children, even after the introduction of treatment with vasopressin, either as desmopressin, or lysine vasopressin spray in one of the early cases.     

Diabetes insipidus with impaired osmotic regulation in septo-optic dysplasia and agenesis of the corpus callosum.

The clinical and endocrinological findings in 24 children with septo-optic dysplasia and/or agenesis of the corpus callosum are described with particular reference to posterior pituitary function. Nine had diabetes insipidus. The prevalence of diabetes insipidus was similar in children with complete and incomplete forms of septo-optic dysplasia. Maintenance of normal osmotic balance was very difficult in six of these children, even after the introduction of treatment with vasopressin, either as desmopressin, or lysine vasopressin spray in one of the early cases.     

Pituitary function in a patient with septo-optic dysplasia and pituitary dwarfism (Kaplan-Grumbach-Hoyt syndrome)

The case of a seventeen-year-old female patient with septo-optic dysplasia and pituitary dwarfism is presented. Mental retardation and epilepsy, in addition to absence of the septum pellucidum, point to a widespread lesion of the central nervous system. There is unilateral hypoplasia of the optic nerve. She is of small stature. The dynamic pituitary tests point to deficiency of GH, TSH and ACTH, and an adequate reserve of prolactin, gonadotrophins and vasopressin. TSH insufficiency is probably of primary pituitary origin.     

Evolving hypopituitarism in children with central nervous system lesions

At the time children with suspected hypopituitarism are seen with a subnormal growth rate, it is expected that testing will demonstrate growth hormone (hGH) deficiency. Seven patients with organic CNS lesions--three with histiocytosis X, one with septo-optic dysplasia, one with neonatal meningitis, one with an anterior encephalocele and meningitis, and one with neurofibromatosis who had normal growth hormone concentrations (greater than 7 ng/mL) despite a subnormal growth rate--were studied. Subsequent retesting 0.5 to 4.6 years later demonstrated the development of growth hormone deficiency. Four of the patients had evidence of other pituitary hormone deficiencies at the time of initial testing whereas two subsequently developed other deficiencies. The initial subnormal growth rate in these children may be secondary to their organic CNS lesion or an evolving hypopituitarism, perhaps with deficient somatomedin generation. These studies point out the need for continued observation and retesting in such patients.     

Sexual precocity in association with septo-optic dysplasia and hypothalamic hypopituitarism.

Sexual precocity in association with abnormalities of the central nervous system is well known, but its occurrence with hypothalamic hypopituitarism is most unusual. We report five females with septo-optic dysplasia, blindness, and multiple pituitary tropic hormone deficiencies: all were growth hormone and adrenocorticotropic hormone deficient; two had diabetes insipidus; one had sexual precocity, and one had early pubertal maturation, whereas three were prepubertal and responded to administration of synthetic gonadotropin-releasing hormone. These children retained ability to secrete gonadotropins despite the presence of anterior hypothalamic disease. Experimental data from primates plus our observations on these patients raise questions about the role of the anterior hypothalamus in gonadotropin secretion in man.     

Optic nerve hypoplasia and hypopituitarism

Optic nerve hypoplasia (ONH) has a wide clinical spectrum. When it is associated with absence of the septum pellucidum, it has been termed septo-optic dysplasia. Over the past 50 years, much has been learned about ONH and its association with pituitary endocrinopathies. Causative factors have been sought that may disrupt development of the optic nerve and the hypothalamic-pituitary axis simultaneously. The endocrinological aspects of ONH require lifelong monitoring and replacement of pituitary hormones when necessary. Children with ONH are also at greater risk for structural abnormalities of the brain, and abnormalities in certain structures are positively correlated with increased risk for pituitary deficiencies. However, it has also been shown that children with ONH and "normal" head imaging can still manifest endocrinopathies. Subsequently, a long-term multidisciplinary approach, involving pediatric specialists in ophthalmology, endocrinology, neurology, and behavioral therapy, is critical to optimize growth and development of all children with ONH.     

Evidence for possible Mendelian inheritance of septo-optic dysplasia

We describe two siblings from a highly consanguineous pedigree with absent mid-line brain structures and hypopituitarism. This raises the possibility of a heritable basis for at least some forms of the septo-optic dysplasia sequence.     

Normal MR appearances of the posterior pituitary in central diabetes insipidus associated with septo-optic dysplasia

Magnetic resonance (MR) imaging of the pituitary in children with central diabetes insipidus usually shows absence of the normal high signal within the posterior gland. The high signal of the normal posterior pituitary is thought to be due to the presence of intra- cellular storage granules of vasopressin. MR imaging has been advocated as a useful investigation to aid in the distinction between central diabetes insipidus and other causes of thirst and polydipsia. We report the case of an infant with central diabetes insipidus in association with septo-optic dysplasia in whom MR imaging showed normal appearances of the posterior pituitary. The mechanism of central diabetes insipidus in this case may be related to a failure of hypothalamic function affecting osmoreception, rather than to a deficiency of vasopressin. Normal MR appearances of the pituitary do not exclude central diabetes insipidus in infants with midline cerebral malformations. Received: 20 November 1995 Accepted: 20 January 1996     

The endocrine spectrum of septo-optic dysplasia

Six children with septo-optic dysplasia were evaluated at the Children's Hospital of Philadelphia. There was a common history of young, nulliparous mothers. The clinical presentation of these children differed according to age of presentation and was a function of the degree and type of hypothalamic-pituitary and ophthalmologic impairment. Endocrine evaluation revealed four of six children to be growth hormone deficient, four of six to have hypothalamic hypothyroidism, and two of four to have elevated prolactin levels. One of the patients demonstrated adrenocorticotropic hormone deficiency, and one had diabetes insipidus. Neuroanatomic findings in the children were variable, but, in general, the rare syndrome did not carry as grave a morbidity as had been reported previously. Our data support a high degree of hypothalamic impairment in septo-optic dysplasia.     

Septo-optic dysplasia and growth hormone deficiency: accelerated pubertal maturation during GH therapy

We report four patients (three male, one female) with septo-optic dysplasia and growth hormone deficiency. All had GH therapy for a period of four to eight years until reaching final height. In all four cases bone maturation during puberty was accelerated (1.4 to 1.9 "years"/year), resulting in a final height which was clearly below the predicted height. The progress of pubertal stages was very short in all patients. In three patients TSH and prolactin release after TRH stimulation were increased. These data support a hypothalamic original of the endocrine disorder. Insufficient GH release, even after repeated GHRH stimulation, is in contrast to this assumption. In one case there was a late manifestation of neurohormonal diabetes insipidus, which indicates the possibility of later disease progression. MR imaging of the brain demonstrated variable malformation of the septum pellucidum, chiasma and nervus opticus or the pituitary gland, respectively.     

Sexual precocity with hypothalamic hypopituitarism.

Two girls, one with septo-optic dysplasia and the other with posttraumatic brain damage, had the unusual combination of human growth hormone, thyrotropin, adrenocorticotrophic hormone, and vasopressin deficiencies that were associated with sexual precocity in one patient and early sexual maturation in the second patient, and of adult follicle-stimulating hormone and luteinizing hormone concentrations. At autopsy, the first patient had optic nerve aplasia, a normal pituitary gland, and some disorganization of myelinated fibers in the hypothalamus. The second patient had a normal thyrotropin and prolactin response to thyrotropin-releasing hormone, plus hyperphagia, deranged thirst mechanism, and temperature instability. These findings suggest that the lesion may be a defective hypothalamic regulation of pituitary hormone secretion. Congenital or traumatic hypothalamic-pituitary lesions may not affect all releasing factors or trophic hormones in a similar fashion.     

Early-onset of septo-optic dysplasia. A case report with follow-up

The case of a nine-month'old girl with septo-optic dysplasia is reported. The patient suffered in neonatal life from severe hypoglycemia, conjugated hyperbilirubinemia and nystagmus. At the age of 2 months ophthalmological examination revealed bilateral optic nerve hypoplasia; at the age of 9 months endocrinological investigations showed GH and ACTH deficiency and substitutive hormone therapy was started. MRI scans demonstrated dilatation of ventricles and pituitary ectopia. At the age of 27 months hypothyroidism due to TSH deficiency developed. The auxological and neurological follow-up is reported. The importance of direct ophthalmoscopy of the optic nerve in neonatal age is stressed: an early diagnosis can favourably influence the outcome of the disease.