We report an 8-year-old proband with severe motor and intellectual disability presenting a variety of dysmorphic features such as microcephaly,
prominent glabella (ridged metopic suture) and congenital distal limb contractures. As well as panhypopituitary insufficiency,
brain defects, e.g. agenesis of corpus callosum, colpocephaly, and pachygyria as well as strabismus and tracheo-laryngeal hypoplasia, were
diagnosed. Genetic examination revealed a normal karyotype and excluded Wolf-Hirschhorn syndrome and subtelomeric deletions.
Chitayat-Hall syndrome was diagnosed based on clinical traits. (Pol J Endocrinol 2010; 61 (3): 318-321)W pracy przedstawiono opis przypadku chorobowego 8-letniej dziewczynki z głębokim opóźnieniem rozwoju psychoruchowego i intelektualnego,
prezentującego szereg różnych cech dysmorficznych, takich jak: małogłowie, wydatna gładzizna oraz wrodzone przykurcze
dystalnych części kończyn. Ponadto u dziecka rozpoznano wielohormonalną niedoczynność przysadki, wady mózgowia, takie jak: agenezja
ciała modzelowatego, nadmiernie szerokie zakręty mózgu oraz kolpocefalia, a także zez, wiotkość krtani i tchawicy. W wykonanych
badaniach genetycznych wykazano prawidłowy kariotyp żeński, wykluczono zespół Wolfa-Hirschhorna oraz delecje subtelomerowe,
ponadto w porównawczej hybrydyzacji genomowej (CGH) nie wykazano nieprawidłowości. Na podstawie całości obrazu klinicznego
postawiono u pacjentki rozpoznanie zespołu Chitayat-Hall. 
(Endokrynol Pol 2010; 61 (3): 318-321

Basiak, Aleksander

Misiak, Blazej

Pesz, Karolina

Smigiel, Robert

English

Via Medica Journals

318OPISY PRZYPADKÓW/CASE REPORTSEndokrynologia Polska/Polish Journal of EndocrinologyTom/Volume 61; Numer/Number 2/2010ISSN 0423–104XRobert Smigiel M.D., Ph.D., Genetic Department, Medical University, Wrocław, tel: +48 71 784 13 26, tel./fax: +48 71 784 00 63,e-mail: smigiel@gen.am.wroc.plPanhypopituitary insufficiency in a patient withclinical diagnosis of Chitayat-Hall syndromeWielohormonalna niedoczynność przysadki u pacjentaz klinicznym rozpoznaniem zespołu Chitayat-HallRobert Smigiel1, Aleksander Basiak2, Blazej Misiak1, Karolina Pesz11Genetics Department, Medical University, Wrocław2Department of Endocrinology and Diabetology for Children and Adolescents, Medical University, WrocławAbstractWe report an 8-year-old proband with severe motor and intellectual disability presenting a variety of dysmorphic features such as micro-cephaly, prominent glabella (ridged metopic suture) and congenital distal limb contractures. As well as panhypopituitary insufficiency,brain defects, e.g. agenesis of corpus callosum, colpocephaly, and pachygyria as well as strabismus and tracheo-laryngeal hypoplasia, werediagnosed. Genetic examination revealed a normal karyotype and excluded Wolf-Hirschhorn syndrome and subtelomeric deletions.Chitayat-Hall syndrome was diagnosed based on clinical traits. (Pol J Endocrinol 2010; 61 (3): 318–321)Key words: Chitayat-Hall syndrome, congenital distal limb contractures, panhypopituitarism, facial dysmorphismStreszczenieW pracy przedstawiono opis przypadku chorobowego 8-letniej dziewczynki z głębokim opóźnieniem rozwoju psychoruchowego i inte-lektualnego, prezentującego szereg różnych cech dysmorficznych, takich jak: małogłowie, wydatna gładzizna oraz wrodzone przykurczedystalnych części kończyn. Ponadto u dziecka rozpoznano wielohormonalną niedoczynność przysadki, wady mózgowia, takie jak: age-nezja ciała modzelowatego, nadmiernie szerokie zakręty mózgu oraz kolpocefalia, a także zez, wiotkość krtani i tchawicy. W wykonanychbadaniach genetycznych wykazano prawidłowy kariotyp żeński, wykluczono zespół Wolfa-Hirschhorna oraz delecje subtelomerowe,ponadto w porównawczej hybrydyzacji genomowej (CGH) nie wykazano nieprawidłowości. Na podstawie całości obrazu  klinicznegopostawiono u pacjentki rozpoznanie zespołu Chitayat-Hall. (Endokrynol Pol 2010; 61 (3): 318–321)Słowa kluczowe: zespół Chitayat-Hall, wrodzone przykurcze dystalnych części kończyn, panhipopituitaryzm, dysmorfia twarzyIntroductionChitayat–Hall syndrome (OMIM #208080) is a rare, se-vere disorder with autosomal recessive inheritance. Theclinical traits are very heterogeneous. The most impor-tant symptoms include neurological anomalies and in-tellectual disability, distal joint contractures and char-acteristic dysmorphic features, as well as respiratory sys-tem and skeletal anomalies and endocrine abnormali-ties concerning the pituitary gland.We present an 8-year-old female proband with se-vere intellectual disability, distinctive facial dysmor-phism: contractures and panhypopituitarism clinicallydiagnosed as Chitayat-Hall syndrome.Case reportAn 8-year-old girl born to a G4P3 was referred to theGenetics Department for genetic counselling becauseof psychomotor delay followed by mental and physicalretardation as well as dysmorphic features. The prop-osita was born to unrelated parents, her family and pre-natal history was unremarkable. Mother excludedknown teratogen exposure during pregnancy. The pa-rameters at birth were as follows: birth weight — 2850 g,OFC (occipitofrontal circumference) — 32 cm, 7 Apgarpoints. The newborn was hospitalized on the neonatalward because of an apnoea episode, hypoglycaemiarespiratory insufficiency and bradycardia. Toxoplasmosis,319Endokrynologia Polska/Polish Journal of Endocrinology 2010; 61 (3)OPISY PRZYPADKÓWcytomegaly infection, and internal defects were exclud-ed. Hearing test results was normal.The hypotonia and retardation of growth develop-ment and distal arthrogryposis were observed in infan-thood. The milestones in psychomotor developmentwere delayed (she started to sit at 2 years of age, walk-ing at 4 years), and her crying was high pitched.Many hospitalizations occurred during early child-hood. The girl was admitted to the Department of En-docrinology for Children and Adolescents for the firsttime at the age of four because of the recurrent hypogly-caemic episodes.  A hormone examination revealed reg-ular tropic hormone levels. Stimulating tests with Syn-acthen and TSH were performed and in both cases theresults were normal. An excessive insulin projection onthe blood glucose curve was not found, although a lowgrowth hormone (GH) level was observed (the noctur-nal profile of GH, dynamic tests with clonidine and glu-cagon). The hypoglycaemic episodes were not observedfor two years. Subesquently, neuroglycopenia duringan infection of the respiratory tract was the reason fora second, sudden hospitalization. Lower ACTH andTSH levels with adrenocortical insufficiency and hy-pothyroidism as well as low GH projection (in the noc-turnal profile and the dynamic tests — below 1 ng/ml)were diagnosed. The above results confirmed panhy-popituitary insufficiency. L-thyroxine, hydrocortisone,and growth hormone were introduced into therapy.MRI of the brain revealed a small pituitary gland, agen-esis of the corpus callosum, mild deformation of thebrain ventricles (colpocephaly), pachygyria, septumpellucidum absence, and the anterior part of cerebralfalx hypoplasia. Additional examinations revealed stra-bismus, tracheo-laryngeal hypoplasia, and abnormalEEG. Metabolic disorders were excluded in GC-MS andtandem MS tests. Normal levels of 7-dehydrocholester-ol in blood serum were revealed.Clinical evaluation at the 8-year-old showed intel-lectual disability and delayed speech development aswell as severe microsomia: body weight 13 kg (7 kg be-low third percentile, –4.3 SDS), height 86 cm (30 cm be-low third percentile, –8.4 SDS), and head circumstance43 cm (7 cm below third percentile, –7.2 SDS). The pa-tient presented a variety of facial dysmorphic featuresincluding microcephaly, bitemporal narrowing, prom-inent glabella (ridged metopic suture), epicanthic fold,ptosis, strabismus, expressionless face, small tippednose, anteverted nares, hypoplastic, low-set ears, highpalate, long philtrum, down-turned corners of themouth, thin upper lip, micrognathia and a short, wideneck (Fig. 1). Moreover, she had small hands and feet,camptodactyly, clinodactyly, distal arthrogryposis, de-formation of the thorax, wide-spaced nipples, scoliosis,and hypoplastic external genitalia.Genetic analysisA venous blood sample was taken from the patient toperform karyotyping and fluorescence in situ hybrid-ization studies. Chromosomal analysis was performedaccording to standard procedures and G-banding at550-band level revealed a normal, female karyotype.FISH studies excluded subtelomeric deletions and Wolf––Hirschhorn syndrome (4p microdeletion). The pa-tient’s DNA was investigated by comparative genomichybridization (Vysis, Abbott Molecular, USA) carried outFigure 1A, B. The phenotype of Chitayat-Hall syndrome ina patient with panhypopituitarismRycina 1A, B. Fenotyp pacjenta z zespołem Chitayat-Halloraz z wielohormonalną niedoczynnością przysadki320Chitayat-Hall syndrome — case report Robert Smigiel et al.OPISY PRZYPADKÓWTable I. A comparison clinical features of Chitayat-Hall syndrome patients with previously described cases and oursTabela I. Dane kliniczne pacjentów z zespołem Chitayat-Hall opisanych w literaturzeClinical traits and other disorders Chitayat Chitayat Wortmann Smigielet al. 1990  et al. 1991 et al. 2007 et al. 2009Pat. 1 Pat. 2 Pat.  1 Pat. 2Square shaped head + + + – + +Narrow forehead + + + – + +Ridges over sutures + + + – + +Small anterior fontanelle + – + – – –Hypertelorism – – – – – –Ptosis – – + – – –Nystagmus – + – – – –Strabismus – – – – + +Myopathic face – – + – + +Depressed nasal bridge + + + – + +Hypoplastic malar areas + + + – + +Highly arched palate + + + – + +Chubby cheeks + + + – + +Retrognathia + + + – + +Ear deformation + + + – + +Posteriorly angulated ears + – + – – +Short neck – + + – + +Increased fatty tissue and decreased muscle mass + + + + + +Ulnar deviation + – + – – –Radio-ulnar synostosis + – – – – –Distal arthrogryposis + + + + + +Adducted thumbs + + + – + +Subluxation of proximal radius + – – – – –Dimples over the knuckles + + + – – –Fingers overlapping (2th, 5th/3rd, 4th) + + + – + +Palmar creases + + + – + –Hypoplasia of thenar and hypothenar + – + – + +Chest deformations + + + – + +Scoliosis + – + – – –Dislocated hips + – + – – –Hallux valgus – – + – – –Hammer toes + – + – – –Respiratory system defects + + + + + +Enlarged thymus – + – – – –Apneic episodes + + + – – +Bradycardia + + + – – +Hypoglycaemia + – – – – +Hypopituitarism + + – – – +Secondary hypothyroidism + – – – – –Hypoplasia of labia minora – – + – – –Cryptorchismus – + – – – –Hydronephrosis – – + – –Cystic dysplastic foci in kidneys – + – – – –Bilateral pelviectasis + – – – – –Dilatation of ureters – – – + – –Physical and mental development delay + + + – + +Seizures + – – – + –Pachygyria + – – – + +Decreased cerebral tissue + – – – – –Enlarged ventricles + – + + – +Subgaleal haemorrhage – – – + – –Epidural haemorrhage – – – + – –Agenesis/hypogenesis of corpus callosum – – – – – +Septum pellucidum absence – – – – – +321Endokrynologia Polska/Polish Journal of Endocrinology 2010; 61 (3)OPISY PRZYPADKÓWaccording to the manufacturer’s protocol. Normal fe-male reference DNA was used as a control. No ratioprofile imbalances were detected in the proband.DiscussionIn 1990 David Chitayat reported two siblings — a broth-er and a sister with distal arthropathy, hypopituitarism,mental retardation, and characteristic pattern of facialdysmorphism [1]. The brother died at the age of threemonths for unknown reasons. The sister developeddeficiency of growth hormone and responded to hor-monotherapy. The occurrence in two sibs of differentsex suggests autosomal recessive inheritance, althoughthe affected gene was not described. One year laterChitayat presented two other siblings with similarsymptoms such as characteristic facial dysmorphic fea-tures and distal arthrogryposis [2]. One of them diedshortly after delivery because of respiratory failure dueto lung hypoplasia. The second sibling developed se-vere mental retardation.Chitayat-Hall syndrome includes a variety of skulland face dysmorphisms such as brachycephaly, micro-cephaly, or trigonocephaly. Cranial sutures are oftenridged and fontanelles begin to close early. The face hasa round shape with full cheeks. Facial features includealso a prominent forehead, low-set, prominent andposteriorly rotated ears with absent or hypoplastic earlobules, short, up-slanting palpebral fissures, telecan-thus, and sparse or decreased eyebrows with lateralhypoplasia. Small, short, and upturned nose with de-pressed nasal bridge or anteverted nares is a commonfinding in Chitayat-Hall syndrome [2, 3]. The clinicalfeatures found in our patient overlap with those report-ed by Chitayat and other authors (Fig. 1, Table I).The most significant features for diagnosis of Chi-tayat-Hall syndrome are congenital distal limb contrac-tures. Bamshad and co-workers defined this anomalyas a consequence of foetal hypokinesis due to congeni-tal myopathies, neuropathies, central nervous systemdisorders, or connective tissue abnormalities [4]. On theother hand, distal arthrogryposis is defined as an in-herited primary limb malformation, characterized bycongenital contractures of at least two areas withoutprimary neurologic and/or muscle disease affecting limbfunction [5, 6]. Chitayat and co-workers used the termdistal arthrogryposis. It is suggested that central ner-vous system anomalies are responsible for the congen-ital contractures in Chitayat-Hall syndrome. In our casewith Chitayat-Hall syndrome we confirm the hypoth-esis that the congenital limb contractures are due tobrain anomalies.The cases described in literature by Chitayat et al.are linked by panhypopituitarism, which was diag-nosed at the age of six in our patient. Pituitary glandabnormalities were confirmed by brain imaging [7, 8].What is interesting is that endocrine tests performedduring the first hospitalization on the endocrinologyward showed normal hormone concentrations. Afterthat, a severe neurohypoglycaemic episode revealedpanhypopituitarism. Substitution treatment was suc-cessful and prevented hypoglycaemic attacks.In the presented case, the girl has clinical traits over-lapping with those observed in Chitayat-Hall syn-drome. The phenotype is highly variable and the generesponsible for it is still unknown. Hence clinical diag-nosis is difficult. We hope that additional reported cas-es will contribute to establishing the diagnostic andtreatment criteria for this rare dysmorphic syndromeand will help to find the affected gene.References1. Chitayat D, Hall JG, Couch RM et al. Syndrome of mental retardation,facial anomalies, hypopituitarism, and distal arthrogryposis in sibs. AmJ Med Genet 1990; 37: 65–70.2. Chitayat D, Hodgkinson KA, Blaichman S et al. Syndrome of mental retar-dation and distal arthrogryposis in sibs. Am J Med Genet 1991; 41: 49–51.3. Wortmann SB, Rodenburg R, Schwahn B et al. Distal joint contractures,mental retardation, characteristic face and growth retardation: Chitayatsyndrome revisited. Genet Couns 2007; 18: 119–123.4. Bamshad M, Jorde LB, Carey JC. A revised and extended classification ofdistal arthrogryposes. Am J Med Genet 1991; 65: 277–281.5. Boles RG. Cleft palate, ptosis, digital anomalies and mental retardation:a new syndrome or a distal arthrogryposis variant? Clin Dysmorphol1999; 8: 63–65.6. Schrander-Stumpel CT, Fryns JP, Schrander JJ et al. Distal arthrogrypo-sis, specific facial dysmorphism and psychomotor retardation: a recog-nizable entity in surviving patients with the fetal akinesia deformationsequence. Genet Couns 1991; 2: 69–75.7. Pisarek H, Pawlikowski M, Kunert-Radek J et al. Expression of soma-tostatin receptor subtypes in human pituitary adenomas – immunohis-tochemical studies. Endokrynol Pol 2009, 60: 240–251.8. Gut P, Kosowicz J, Ziemnicka K et al. The incidence of the pituitary au-toantibodies in Addison disease. Endokrynol Pol 2008, 59: 490–494.

Wielohormonalna niedoczynność przysadki u pacjenta z klinicznym rozpoznaniem zespołu Chitayat-Hall

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Wielohormonalna niedoczynność przysadki u pacjenta z klinicznym rozpoznaniem zespołu Chitayat-Hall

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