Indian Journal of Pathology and Microbiology

CASE REPORT
Year
: 2012  |  Volume : 55  |  Issue : 1  |  Page : 100--103

Pallister-Hall syndrome presenting as an intrauterine fetal demise at 39 weeks' gestation


Sunil Jaiman1, Himabindu Nalluri2, Nuzhat Aziz3, Geeta Kolar4,  
1 Department of Anatomic and Perinatal Pathology, Fernandez Hospital, Bogulkunta, Abids, Hyderabad, India
2 Department of Anatomy, Bhaskar Medical College, Moinabad, RR District, India
3 Department of Obstetrics, Fernandez Hospital, Bogulkunta, Abids, Hyderabad, Andhra Pradesh, India
4 Department of Fetal Medicine, Fernandez Hospital, Bogulkunta, Abids, Hyderabad, Andhra Pradesh, India

Correspondence Address:
Sunil Jaiman
Department of Anatomic Pathology, Fernandez Hospital, Plot # 769, Road # 44, Jubilee Hills, Hyderabad - 500 033, Andhra Pradesh
India

Abstract

Pallister-Hall syndrome (PHS) is a pleiotropic autosomal-dominant malformation syndrome rarely presenting with genitourinary malformations. Literature has recorded 14 cases of PHS with genitourinary findings out of which only six have been females presenting with hydrometrocolpos and/or vaginal atresia. Fetal autopsy findings on a 39 weeks«SQ» gestation including demonstration of corticotroph deficiency in the pituitary, along with the review of literature is being presented here. None of the earlier literature pertaining to PHS with hydrometrocolpos and/or vaginal atresia describes an intrauterine fetal demise due to corticotroph deficiency.



How to cite this article:
Jaiman S, Nalluri H, Aziz N, Kolar G. Pallister-Hall syndrome presenting as an intrauterine fetal demise at 39 weeks' gestation.Indian J Pathol Microbiol 2012;55:100-103


How to cite this URL:
Jaiman S, Nalluri H, Aziz N, Kolar G. Pallister-Hall syndrome presenting as an intrauterine fetal demise at 39 weeks' gestation. Indian J Pathol Microbiol [serial online] 2012 [cited 2020 Nov 27 ];55:100-103
Available from: https://www.ijpmonline.org/text.asp?2012/55/1/100/94873


Full Text

 Introduction



Pallister-Hall syndrome (PHS) (MIM 146510) is a pleiotropic disorder of human development initially described in 1980. It is a rare, autosomal-dominant malformation syndrome with a wide spectrum of severity including neonatal lethality. [1] The major clinical diagnostic criteria for PHS require the presence of a hypothalamic hamartoma, central (i.e., insertional or mesoaxial) polydactyly, post-axial polydactyly (PAP) types A and B, and bifid epiglottis. [2] PHS is caused by mutations in GLI3, a gene encoding a zinc finger transcription factor that regulates downstream target genes in the sonic hedgehog signaling pathway. There is nonsense frameshift and single splice mutations in the middle third of GLI3, which includes exons 13, 14, and part of 15. [3] Many cases are sporadic and familial cases have been reported with variable phenotype.

A third gravida with 39 weeks' gestation was referred to our hospital with an unexplained intrauterine fetal demise (IUFD) on which an autopsy was performed. The case demonstrated features of PHS with genitourinary malformations. Genitourinary malformations are relatively uncommon with PHS and only a total of 14 cases have been described in the literature out of which six have been females. [4],[5] Further evaluation, especially Immunohistochemistry (IHC) examination of the pituitary gland, demonstrated corticotroph deficiency. This latter feature has never been described in the earlier literature pertaining to PHS with hydrometrocolpos and or vaginal atresia.

 Case Report



This infant girl with an unexplained IUFD at 39 weeks' gestation born to South Asian healthy non-consanguineous parents was referred for an autopsy. The mother, 27 years of age, had a history of two miscarriages at three months' amenorrhea. She is a non-smoker, non-alcohol dependent without history of narcotic abuse, drug intake, or exposure to noxious environmental conditions. A third trimester ultrasound scan at 35 weeks detected a large intra-abdominal cyst suggestive of hydrometrocolpos and PAP. Amniocentesis revealed a normal female karyotype 46, XX. There is no family history of polydactyly and the X-rays of the parents of the proband under discussion are normal.

A perinatal necropsy was conducted by employing the Rokitansky procedure and the fetus displayed grade I maceration. External examination revealed hypertelorism, a short nose, broad nasal bridge, down turned corners of the mouth, and bilateral low set ears [Figure 1]. There was heptadactyly of the right hand with PAP type A and syndactyly between fifth, sixth, and seventh digits, while the left hand and foot showed hexadactyly with PAP type A [Figure 2]. There was nail hypoplasia and brachydactyly of all the digits, with the hand at 1 and foot at 29 th centile. Perineal inspection revealed external genitalia of the female type but with rudimentary clitoris and labia minora. There was a single urethral orifice instead of a separate vaginal introitus and urethral ostium. The anal orifice was patent but ectopic [Figure 3]. The Crown Heel Length was 475 mm; Crown Rump Length, 320 mm; and the Head Circumference (HC), 325 mm at 43 rd , 21 st , and 24 th percentile, respectively.{Figure 1}{Figure 2}{Figure 3}

Internal examination revealed hydrometrocolpos with vaginal atresia and ectopic anteriorly placed anal canal [Figure 3]. The uterus was small and globular, cephalic to a massively dilated vagina with stretched fallopian tubes and compressed bilateral ovaries. There was abnormal lobation of the lungs with two lobes in the right and a single partial fissure without lobation in the left lung. The pulmonary veins were bilaterally single. The left common carotid and the left subclavian artery appeared to be arising as a common trunk. There was atrial septal defect of the septum primum type. The epiglottis was bifid [Figure 4]. The brain revealed a 3 × 3 cm hypothalamic hamartoma [Figure 5] and the pituitary was hypoplastic. The weights of most of the internal organs were less than 25 th centile. The thyroid and the adrenal glands were severely hypoplastic. The thyroid weighed 0.7 g against an expected weight of 1.6 g. The adrenals were 3.8 g against the expected weight of 7.4 g and were at the 7 th centile. Histopathologic examination showed the hypothalamic hamartoma to be composed of haphazardly arranged neurons lacking the normal laminar organization. Routine immunohistochemical staining was done on sections from paraffin-embedded tissue using the avidin-biotin complex method. The hamartoma did not stain for Glial Fibrillary Acidic Protein, Neurofilament, Synaptophysin, or Epidermal Growth Factor Receptor confirming the hamartomatous nature of the lesion [Figure 6]. The IHC of the pituitary gland sections showed growth hormone secreting somatotrophs along with follicle stimulating and luteinizing hormone gonadotrophs; however, prolactin-secreting lactotrophs and adrenocorticotrophin-secreting corticotrophs were absent in the adenohypophysis [Figure 6].{Figure 4}{Figure 5}{Figure 6}

 Discussion



PHS manifests with a myriad of congenital abnormalities such as hypothalamic hamartoma, central (i.e., insertional or mesoaxial) polydactyly, PAP types A and B, and bifid epiglottis. [2] PHS has been categorized as a member of the CAVE (Cerebro Acro Visceral Early lethality) group of disorders, with few affected individuals having an early lethality phenotype. [2] This early lethality is most likely attributable to hypopituitarism that is caused by pituitary or hypothalamic dysplasia or severe airway malformations such as laryngotracheal clefts. In addition, imperforate anus can cause serious complications if not recognized promptly. [2]

The review of literature has revealed that only six cases of PHS have been females presenting with hydrometrocolpos and/or vaginal atresia. Though our case resembles the earlier cases described in the literature, summarized in [Table 1], none of the cases, however, describe an IUFD due to corticotroph deficiency.{Table 1}

The various human pituitary hormone producing cells during embryonal development have been well determined by IHC stains. The corticotrophs are the first cells to differentiate in human fetal pituitary at around five weeks of gestation. The Somatotrophs appear at around eight to nine weeks, followed by the Thyrotrophs and the Gonadotrophs at twelve to fifteen weeks. The Lactotrophs, although seen in small numbers as early as 12 weeks, are only fully recognizable at 23 weeks. [6] The expression of the six pituitary hormones is orchestrated by transcription factors including HESX1, PROP1, POU1F1, LHX3, LHX4, PITX1, PITX2, SOX2, and SOX3. The expression pattern of these transcription factors dictates the phenotype that results when the gene encoding the relevant transcription factor is mutated. Isolated adrenocorticotrophin hormone deficiency has an autosomal recessive inheritance and the gene responsible is TPIT, while PHS is autosomal dominant disorder involving GLI3.

The differential diagnosis for hydrometrocolpos and PAP include McKusick-Kaufman syndrome (MKKS) which is an autosomal recessive disorder characterized by hydrometrocolpos secondary to vaginal atresia, imperforate anus, and congenital heart defects. The gene that encodes a putative chaperonin molecule has been mapped to 20p12. Mutation of this gene has been suggested to interfere with ATP hydrolysis and has been thought to have a role in limb, cardiac, and reproductive system development. MKKS does not show hypothalamic hamartoma, bifid epiglottis, and pituitary hypoplasia.

Bardet-Biedl syndrome (BBS), an autosomal recessive disorder, is characterized by rod-cone dystrophy (>90%), truncal obesity (72%), PAP, cognitive impairment, male hypogonadotropic hypogonadism, complex female genitourinary malformations, and renal abnormalities. [7] Renal disease is a major cause of morbidity and mortality. Hypothalamic hamartoma and bifid epiglottis are extremely rare manifestations of BBS. [8]

Our case provides compelling evidence that all prenatally diagnosed cases of PAP and hydrometrocolpos with vaginal atresia in females should undergo a prenatal cranial scans, preferably magnetic resonance imaging (MRI), as an adjunct for the exclusion of a hypothalamic hamartoma and pituitary hypoplasia in order to exclude PHS. Failure to do so may result in an unexpected IUFD as in our case or a neonatal death due to implicit hypopituitarism caused by pituitary or hypothalamic dysplasia. An urgent investigation for the presence of pituitary dysfunction, especially assessment for cortisol deficiency, must be performed in (a) individuals who have no family history of PHS and in (b) individuals who have family members with PHS and cortisol deficiency since adrenal crisis can be lethal in infants who have not undergone proper evaluation and treatment for adrenal insufficiency. [2]

 Acknowledgment



A special thanks to Dr. Sundaram Challa and Dr. Megha Uppin from Nizams Institute of Medical Sciences, Hyderabad, India and Dr. Swarnalata G from Apollo Hospitals, Hyderabad, India, for assisting with the performance of Immunohistochemistry stains. The authors acknowledge the help of Dr. Vijaya of care Hospital, Nampally, Hyderabad, for preparing blocks and slides for us. The authors also thank Dr. Praveen Nirmalan, Head, Clinical Research, and Ruth Sireesha, Secretary, Academics Department, Fernandez Hospital, Hyderabad, India, for critical reading of the manuscript.[10]

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