GAPO syndrome with pansutural ... - BMJ Case Reports

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CASE REPORT

GAPO syndrome with pansutural craniosynostosis leading to intracranial hypertension Nishant Goyal, Hitesh Gurjar, Bhawani Shankar Sharma, Manjari Tripathi, P Sarat Chandra Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, India Correspondence to Professor Poodipedi Sarat Chandra, [email protected]

SUMMARY GAPO syndrome stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). To date, only about 35 cases of this extremely rare syndrome have been reported. Craniosynostosis/ craniostenosis is a condition with an abnormal head shape due to premature fusion of the calvarial sutures and can be either non-syndromic or syndromic. Overall, craniosynostosis has an incidence of about 1 in 2500 live-births. We present a patient with GAPO syndrome in association with craniosynostosis along with intracranial hypertension, which was the cause of her headache. To the best of our knowledge, this is the first such association in the literature. BACKGROUND GAPO syndrome is a rare entity, which stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). The patient with this syndrome has a peculiar premature geriatric appearance in addition to other typical facial characteristics such as frontal bossing, midfacial hypoplasia and the absence of eyebrows, eyelashes and hair.1 Although this distinctive phenotype can be diagnosed in most patients in infancy, only about 35 cases have been reported since it was first described in 1947 by Anderson and Pindborg (table 1).1 2 Several singular associations such as dilated cardiomyopathia, pulmonary hypertension, prognathia and ankyloglossia were also recently reported.3 4 We present a patient with GAPO syndrome in association with pansutural craniosynostosis along with intracranial hypertension. To the best of our knowledge, this is the first such association in the literature.

CASE PRESENTATION

To cite: Goyal N, Gurjar H, Sharma BS, et al. BMJ Case Rep Published online: [please include Day Month Year] doi:10.1136/bcr-2013201727

A 19-year-old female patient of GAPO syndrome was referred to the neurosurgical clinic with headache. She was the youngest of the four siblings born to healthy but consanguineous parents (first-degree cousins; figure 1). According to the parents, the child was apparently normal until the age of 2 years, when she started losing her scalp hair. She became completely bald over the next 2 years (figure 2). Around the same time, she started complaining of visual disturbances. She had slight mental delay and her physical examination showed distinctive facies such as microcephaly, frontal bossing, prematurely aged face, depressed nasal bridge, protruding eyes, micrognathia, total alopecia, absent eyebrows (figure 3A– C) and eyelashes and failure of tooth eruption (pseudoanodontia; figure 4B,C). In addition, she had

Goyal N, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201727

macroglossia (figure 3A–C). She had a short stature with a height of 122 cm and had a disproportionate body built. She had a stooping posture with lumbar scoliosis having convexity to the left. Her limbs were thick and had a doughy feel. Her cardiovascular system examination and respiratory system examination were within normal limits. Her echocardiogram revealed no abnormality. Her breasts were maldeveloped and she had no axillary or pubic hair. Her body hair was sparse. On pelvic examination, her labia minora were hypertrophied without palpable gonads. Her ophthalmological examination revealed congenital glaucoma with healing hydrops, buphthalmos, keratoconus with Haab’s striae and optic atrophy. She had no perception of light in both her eyes. Her fundi could not be examined due to a fibrovascular band extending nasally.

INVESTIGATIONS The x-ray of her dorsolumbar spine revealed fused L2–L3 vertebrae and left-sided scoliosis with compensatory dorsal curve. A skin biopsy revealed an unremarkable epidermis with deposition of amorphous eosinophilic PAS positive substance in the papillary dermis and around the follicles. Stains for elastin revealed reduction and fragmentation of elastic fibres in the reticular dermis.

TREATMENT The patient was diagnosed as having craniosynostosis (figure 4A) with raised intracranial pressure and bifrontal advancement under general anaesthesia was planned. Initially, she refused surgery but came back to us 1 year later, complaining of increase in the severity of the pain and agreed to undergo surgery. The patient had a difficult intubation due to macroglossia. The bifrontal bone flap had to be raised in three pieces because the underlying dura was densely adherent to the bone. Intraoperatively, a dural tear occurred while raising the bone flap. Brain bulge was present as the dura was opened, thereby confirming the preoperative impression of intracranial hypertension. Bifrontal advancement along with multiple stave osteotomies was carried out using a miniplate and screws (figure 4D,E). The patient was extubated and shifted to the intensive care unit. However, due to tongue fall secondary to macroglossia, the patient could not maintain oxygen saturation and had to be reintubated. A tracheostomy was carried out on the fourth postoperative day. Tracheal decannulation was carried out and the patient was discharged on postoperative day 21. 1

2 Authors

Sex

Consanguinity

Growth retardation

Alopecia

Pseudoanodontia

Optic atrophy

Bossing of head

Prominent scalp veins

Enlarged ventricles

Anderson and Pindborg, 1947 Fuks et al 1978 Shapira, 1982 Da Silva, 1984 Tipton and Gorlin, 1984 Gagliardi et al 1984

F F

NA +

+ +

+ +

+ +

+ +

+ +

NA +

HCP ? slightly dilated

F F M M M F

− − + + + +

+ + + + + +

+ + + + + +

+ + + + + +

− − − − − +

+ + + + + +

NA + − − − +, scalp venous malformation

F M M F M F F M M M F M M F M M M M F F F F M F M M M F F

+ + + + + − − − − − − − + + + + + + + NA + + + + + + + + +

+ + + + + + + + + + + NA + + + + + + + + + + + + + + + + +

+ + + + + + + + + + + + + + + + + + + + + + + + + + + + +

+ + + + + + + + + NA NA + + + + + + + + + + + + + + + + + +

− − − − − + − − +, myopia − − NA + − − + − − − − + − + − −, glaucoma, buphthalmos +, amaurosis −, optic disc pallor +, nystagmus, optic disc pallor +, glaucoma, buphthalmos, keratoconus

+ + + NA NA + + + NA + + NA NA + NA + NA NA NA + + + + + + + + + +

NA NA NA + NA NA − + NA + − NA NA + + + + + NA + − − − NA NA +, craniofacial vascular malformation + + +

− Slightly dilated + + + Bulging fontanelle closed at 6 months − − − − NA NA + NA NA NA NA NA NA NA + + NA NA NA NA NA NA NA − NA

Dellac, 1990 Manouvrier- Hanu, 1987 Wajntal et al 1990 Sayli and Gul, 1993

Phadke et al 1994 Sandgren, 1995 Moriya et al 1995 Suyli and Gul, 1996 Baxova, 1997


Meguid et al 1997 Mullaney et al 1997 Bacon et al 1999 Goucha et al 2000 Orbak et al 2002 Rim and Paula, 2005 Silveira et al 2006 Goloni- Bertollo et al 2008

Demirgunes, 2009 Kocabay, 2009 Castrillon-Oberndorfer, 2010 Nanda et al 2010 Present study

F, female; M, male; NA, not applicable; ?, indicates doubtful.

NA NA −

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Table 1 Clinical features of patients of GAPO syndrome in the published literature

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Figure 1 Family tree of the patient, showing that the patient was a result of a consanguineous marriage ( parents were first degree cousins).

OUTCOME AND FOLLOW-UP Her headache improved significantly in the postoperative period. She stays on follow-up 3 months after the surgery and reports significant improvement in her headache.

DISCUSSION GAPO syndrome was first described as ectodermal dysplasia with craniofacial dysostosis by Anderson and Pindborg5 in 1947. In 1984, Tipton and Gorlin6 named it GAPO syndrome (growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O)). Based on the published literature, growth retardation, alopecia and pseudoanodontia occur consistently in these patients. However, optic atrophy is not reported so often. In addition, ocular anomalies other than optic atrophy have been reported in many cases such as glaucoma, buphthalmos and myopia. Therefore, Meguid et al7 suggested that the ‘O’ in the acronym should stand for ocular manifestations. The present case also had buphthalmos, keratoconus and glaucoma apart from optic atrophy. Patients with GAPO syndrome have a typical facial appearance that includes a wide anterior fontanelle, bossed forehead, depressed nasal bridge, micrognathia, midface hypoplasia, protruding lips and auricles, anteverted nostrils, hypertelorism, absence of the eyebrows, eyelashes and hair and protruding eyes due to shallow orbita.3 4 Our patient had the typical facial features of GAPO syndrome (figure 3A–C). In addition, she also

had macroglossia. She had craniosynostosis with intracranial hypertension, which was the cause of her headache. The headache was relieved by bifrontal reconstruction. Craniosynostosis or premature fusion of the calvarial sutures has an incidence of approximately 1 in 2500 live-births; and has traditionally been classified into non-syndromic or syndromic types based on phenotypic descriptions.8 9 The children considered non-syndromic often have single-suture synostosis without other associated abnormalities. They account for 85% of all cases9 and include premature fusion of sagittal suture (scaphocephaly), unicoronal ( plagiocephaly) or bicoronal (brachycephaly) sutures, metopic suture (trigonocephaly), unilateral lambdoid suture ( posterior plagiocephaly) or acrocephaly (fusion of bilateral coronal suture and anterior sagittal sutures).8 Patients of syndromic craniosynostosis are more likely to have premature fusion of multiple sutures, harbour other skeletal abnormalities and have a strong family history. Syndromic craniosynostosis accounts for the remaining 15% and includes more than 64 sporadic craniofacial syndromes such as Crouzon, Apert, Pfeiffer’s, Saethre-Chotzen and Carpenter to name a few.8–11 Crouzon syndrome has an incidence of 1 in 25 000 live-births and consists of the classic triad of bicoronal synostosis, midfacial hypoplasia an exophthalmos. Apert syndrome has an incidence of 1 in 100 000 to 1 in 160 000 live-births and has bicoronal synostosis and mental retardation with severe syndactylies of hands and feet.9 11 Both Crouzon and Apert syndromes have been linked to Fibroblastic Growth Factor Receptor type 2 (FGFR2) mutations.9 Pfeiffer’s syndrome has features including coronal synostosis along with broad fingers and toes and an association with FGFR1 gene has been found.9 11 SaethreChotzen syndrome has coronal synostosis with limb and facial abnormalities; and is caused by loss-of-function mutations in the TWIST gene.9 11 Risk for raised intracranial pressure (intracranial hypertension) is higher with syndromic craniosynostosis than with non-syndromic craniosynostosis.9–11 The frequency varies with the type of syndrome and has been quoted to be 62.5% for Crouzon’s syndrome and 45% for Apert’s syndrome.11 The contemporary standard of care dictates the treatment of almost all patients for cosmetic indications.10 As syndromic craniosynostosis is characterised essentially by posterior displacement of the forhead and midface, the treatment of this condition primarily involves frontal and facial advancement either separately or simultaneously.11 This is often augmented with stave osteotomies in order to provide more space.

Figure 2 Patient had a normal appearance at the age of 1 year (A). By the age of 5 years, she completely lost her hair and stopped growing in height (B). Goyal N, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201727

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Figure 3 Clinical photographs of the patient (A, B and C) showing distinctive facies such as microcephaly, frontal bossing, prematurely aged face, depressed nasal bridge, protruding eyes, micrognathia, total alopecia, absent eyebrows and eyelashes and macroglossia.

The inheritance pattern in familial cases for all the aforementioned syndromes, known to be associated with craniosynostosis appears to be autosomal dominant except for Carpenter syndrome, which has an autosomal recessive pattern of inheritance.9 GAPO syndrome seems to have an autosomal recessive pattern of inheritance. Wajntal et al12 demonstrated the presence of excess homogenous amorphous hyaline material in all organs and interstitia as well as in serosal membranes. The accumulation of this excess hyaline material was demonstrated in the skin biopsy in our case and its accumulation might have been the cause of premature fusion of the calvarial sutures, thereby leading to craniosynostosis. This is the first instance of association of craniosynostosis with GAPO syndrome. The possibility of a causal, rather than a chance association is more likely for the simultaneous occurrence of these two rare conditions. The patients with GAPO syndrome are reported to have reduced life span and most of them die in the third or fourth decade of life;2 6 7 12 this has been proposed to be related to generalised interstitial fibrosis and atherosclerosis.2 12 In our case, this patient of GAPO syndrome had headache due to intracranial hypertension and associated craniosynostosis. 4

To the best of our knowledge, this is the first such case in the literature.

Learning points ▸ GAPO syndrome is a rare entity, which stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). ▸ GAPO syndrome seems to have an autosomal recessive pattern and the patients with this disorder have a reduced life span and most of them die in the third or fourth decade of life. ▸ Craniosynostosis or premature fusion of calvarial sutures can be of two types, that is, non-syndromic and syndromic. ▸ A patient of GAPO syndrome can rarely present with intracranial hypertension and multisutural craniosynostosis, as seen in our case. Such a patient can benefit from bifrontal advancement to relieve intracranial pressure. Goyal N, et al. BMJ Case Rep 2014. doi:10.1136/bcr-2013-201727

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Figure 4 Preoperative images of the patient, three-dimentional reconstruction of head CT showing pansutural craniosynostosis (A), X0-rays of the patient showing pseudoanodontia (B and C). Intraoperative image (D) showing bifrontal advancement with the subgaleal skin flap reflected and postoperative CT scan (E) showing evidence of bifrontal craniotomy and multiple strip craniectomies.

Contributors MT initially reviewed the patient at the out patient clinic. NG and PSC had the idea for the article. HG performed the literature search. NG and HG drafted the article, which was revised critically for important intellectual content by PSC and BSS. Final approval of the version to be published was given by PSC, MT and BSS. PSC is the guarantor (the contributor who accepts full responsibility for the finished article, had access to any data, and controlled the decision to publish). Competing interests None.

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Patient consent Obtained. Provenance and peer review Not commissioned; externally peer reviewed

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REFERENCES

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Castrillon-Oberndorfer G, Seeberger R, Bacon C, et al. GAPO syndrome associated with craniofacial vascular malformation. Am J Med Genet Part A 2010;152A:225–7. Nanda A, Al-Ateeqi WA, Al-Khawari MA, et al. GAPO syndrome: a report of two siblings and a review of literature. Pediatr Dermatol 2010;27:156–61. Demirg€unes EF, Ersoy-Evans S, Karaduman A. GAPO syndrome with the novel features of hypertension, ankyloglossia, and prognathism. Am J Med Genet Part A 2009;149A:802–5.


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Kocabay G, Mert M. GAPO syndrome associated with dilated cardiomyopathy: an unreported association. Am J Med Genet Part A 2009;149A:415–16. Andersen TH, Pindborg JJ. Et tilfaelde of total pseudoanodontia forbindelsemedcraniedeformitet, dvaergvaekst og ektodermal dysplasia. Odont Tids 1947;55:484–93. Tipton RE, Gorlin RJ. Growth retardation, alopecia, pseudoanodontia, and optic atrophy—the GAPO syndrome. Am J Med Genet 1984;19:209–16. Meguid NA, Afifi HH, Ramzy MI, et al. GAPO syndrome: first Egyptian case with ultrastructural changes in the gingiva. Clin Genet 1997;52:110–15. Andar U, Mokal N. Craniofacial deformities (craniostenosis). In: Tandon PN, Ramamurthi R, eds. Textbook of neurosurgery. New Delhi: Jaypee Brothers Medical Publishers Ltd, 2012:224–30. Drzymalski D, Proctor M. Gentics of craniosynostosis. In: Winn HR, ed. Youmans neurological surgery. Philadelphia: Elsevier Saunders, 2011:1936–9. Persing JA, Jane JA Sr, Piatt JH Jr. Craniosynostosis. In: Winn HR, ed. Youmans neurological surgery. Philadelphia: Elsevier Saunders, 2011:1940–54. Matthew DS, Daniel M, Dominique R. Syndromic craniosynostosis. In: Winn HR, ed. Youmans neurological surgery. Philadelphia: Elsevier Saunders, 2011:1955–64. Wajntal A, Koifmann CP, Mendonca BB, et al. GAPO syndrome (McKusick 23074). A connective tissue disorder: report on two affected sibs and on the pathologic findings in the older. Am J Med Genet 1990;37:213–23.

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