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  Table of Contents    
CASE REPORT  
Year : 2012  |  Volume : 55  |  Issue : 1  |  Page : 100-103
Pallister-Hall syndrome presenting as an intrauterine fetal demise at 39 weeks' gestation


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

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Date of Web Publication11-Apr-2012
 

   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' 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.

Keywords: Corticotroph deficiency, genitourinary malformations, pituitary hypoplasia

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;55:100-3

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 2019 Dec 6];55:100-3. Available from: http://www.ijpmonline.org/text.asp?2012/55/1/100/94873



   Introduction Top


 Pallister-Hall syndrome More Details (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 Top


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: Hypertelorism, short nose, broad nasal bridge, down turned corners of the mouth, and bilateral low set ears

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Figure 2: Heptadactyly of the right hand with post-axial polydactyly and syndactyly between fifth, sixth, and seventh digits and hexadactyly of left hand with post-axial polydactyly. Upper panel: Macroscopic picture. Lower panel: Roentgenogram

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Figure 3: Left panel: External genitalia of the female type with rudimentary clitoris and labia minora. A single urethral orifice instead of a separate vaginal introitus and urethral ostium; ectopic but patent anal orifice. Right panel: Hydrometrocolpos

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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 tube More Detailss 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: Bifid epiglottis

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Figure 5: Hypothalamic hamartoma

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Figure 6: Upper panel: The IHC of the pituitary gland sections show absent adrenocorticotrophin secreting corticotrophs (×40 and ×100), positive staining for somatotrophs (×200), gonadotrophs (both ×200), and absent lactotrophs in the adenohypophysis (×200). Lower panel: Hypothalamic hamartoma (×100 and 200) composed of haphazardly arranged neurons lacking the normal laminar organization negative for Synaptophysin (SYP ×200), Glial Fibrillary Acidic Protein (GFAP ×400), Neurofilament (NF ×200), and Epidermal Growth Factor Receptor (EGFR ×200) confirming the hamartomatous nature of the lesion

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   Discussion Top


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: Clinical characteristics of patients with PHS

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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 More Details (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 Top


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]

 
   References Top

1.Hall JG, Pallister PD, Clarren SK, Beckwith JB, Wiglesworth FW, Fraser FC, et al. Congenital hypothalamic hamartoblastoma, hypopituitarism, imperforate anus and postaxial polydactyly-a new syndrome? Part I: Clinical, causal, and pathogenetic considerations. Am J Med Genet 1980;7:47-74.  Back to cited text no. 1
[PUBMED]    
2.Biesecker LG. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. Gene Reviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2000 May 25 [Last updated on 2010 Jun 15]. [Last accessed on 2011 Jan 25].  Back to cited text no. 2
    
3.Johnston JJ, Olivos-Glander I, Killoran C, Elson E, Turner JT, Peters KF, et al. Molecular and clinical analyses of Greig cephalopolysyndactyly and Pallister-Hall syndromes: Robust phenotype prediction from the type and position of GLI3 mutations. Am J Hum Genet 2005;76:609-22.  Back to cited text no. 3
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4.Narumi Y, Kosho T, Tsuruta G, Shiohara M, Shimazaki E, Mori T, et al. Genital abnormalities in Pallister-Hall syndrome: Report of two patients and review of the literature. Am J Med Genet Part A 2010;152:3143-7.  Back to cited text no. 4
    
5.McCann E, Fryer AE, Craigie R, Baillie C, Ba'ath ME, Selby A, et al. Genitourinary malformations as a feature of the Pallister-Hall syndrome. Clin Dysmorphol 2006;15:75-9.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Lopes MB, Pernicone PJ, Scheithauer BW, Horvath E, Kovacs K. Pituitary and sellar region. In: Mills SE, editor. Histology for pathologists. 3 rd ed.Philadelphia: Lippincott, Williams and Wilkins; 2007. p. 332.  Back to cited text no. 6
    
7.Waters AM, Beales PL. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Last Revision: November 18, 2010. [Last accessed 20 2011 Feb 11].  Back to cited text no. 7
    
8.Stevens CA, Ledbetter JC. Significance of bifid epiglottis. Am J Med Genet A 2005;134:447-9.  Back to cited text no. 8
[PUBMED]  [FULLTEXT]  
9.Kos S, Roth K, Korinth D, Zeilinger G, Eich G. Hydrometrocolpos, postaxial polydactyly, and hypothalamic hamartoma in a patient with confirmed Pallister-Hall syndrome: A clinical overlap with McKusick-Kaufman syndrome. Pediatr Radiol 2008;38:902-6.  Back to cited text no. 9
[PUBMED]  [FULLTEXT]  
10.Unsinn KM, Neu N, Krejci A, Posch A, Menardi G, Gassner I. Pallister-Hall syndrome and McKusick-Kaufmann syndrome: One entity? J Med Genet 1995;32:125-8.  Back to cited text no. 10
[PUBMED]  [FULLTEXT]  

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Correspondence Address:
Sunil Jaiman
Department of Anatomic Pathology, Fernandez Hospital, Plot # 769, Road # 44, Jubilee Hills, Hyderabad - 500 033, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.94873

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
    Tables

  [Table 1]

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