Indian J Pediatr DOI 10.1007/s12098-015-1990-1
SCIENTIFIC LETTER
Infantile Systemic Hyalinosis with Mutation in ANTXR2 Dhanya Lakshmi Narayanan 1 & Shubha R. Phadke 1
Received: 4 July 2015 / Accepted: 10 December 2015 # Dr. K C Chaudhuri Foundation 2016
To the Editor: Infantile systemic hyalinosis (OMIM 236490) is a rare autosomal recessive disorder characterized by deposition of hyaline in skin, gingiva, adrenals, skeletal muscles and gastro intestinal tract [1, 2]. It presents in a new born or in early infancy with painful movements, joint contractures, gingival nodules, progressive skin thickening and hyperpigmented patches over bony prominances [3] and is caused by homozygous or compound heterozygous mutations in ANTXR2 on 4q21, which encodes capillary morphogenesis protein 2(CMG2) [4]. Mutation analysis is essential in confirming the diagnosis and offering prenatal diagnosis. We report a case of 2-mo-old boy with a homozygous mutation in ANTXR2. To our knowledge this is the first mutation proven case being reported from North India. A 2-mo-old boy who was the second child of third degree consanguineous parents had excessive cry during handling noticed since birth. Antenatal period of the mother was uneventful. He also had progressively increasing joint contractures of both elbows, ankles and knees with thick and shiny skin. He did not have chronic diarrhea and was gaining weight adequately. His elder sibling was a 3-y-old girl who was normal. On examination, he was very irritable and cried when touched. He had hyperpigmented macules over dorsum of hands over the knuckles, knees and on both malleoli. Skin
* Shubha R. Phadke [email protected]; [email protected] 1
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute, Lucknow, Uttar Pradesh 226014, India
was indurated and thickened (Fig. 1). He had contracture of bilateral elbows, knees and ankles. He did not have gingival nodules or perianal papules or tags. His weight was 4 kg, length 52 cm and head circumference 34 cm (Normal for age). He did not have hepatosplenomegaly. Routine hematology and serum chemistry were normal. Radiographs did not show osteopenia or lytic lesions. Mutation analysis of ANTXR2 was done by Sanger sequencing and a homozygous c.1073_1074insC in exon 13 was identified. This mutation is a previously described disease causing mutation. Infantile systemic hyalinosis was first described by Landing and Nadorra in 1986 [1]. Systemic infantile hyalinosis should be suspected in a newborn or infant presenting with excessive cry during handling, skin thickening, hyperpigmented skin over bony prominences and joint contractures [1, 2]. Other features include gingival thickening, pearly white skin papules, perianal fleshy lesions and failure to thrive. Thickened skin can be seen in other conditions like Winchester syndrome, congenital fascial dystrophy, infantile restrictive dermopathy, Farber disease, I cell disease and mucolipidosis III A. The presence of characteristic purplish patches over the malleoli, metacarpophalangeal joints, elbow and spine is a distinctive clinical clue that helps to establish the diagnosis. Till date 25 different mutations in ANTXR2 have been described [5]. Two cases were reported from India previously, but molecular diagnosis was not done. Since it is inherited in an autosomal recessive manner, there is 25 % chance of recurrence in subsequent pregnancies. Hence, clinical suspicion and molecular diagnosis is very essential to provide prenatal diagnosis in subsequent pregnancies.
Indian J Pediatr Compliance with Ethical Standards Conflict of Interest None. Source of Funding None. Consent Informed consent from the relatives of the patient has been obtained.
References 1. Fig. 1 Photograph of the child showing (a) hyperpigmented macules on knuckles (b) hyperpigmented macules on medial malleoli (c) contractures of joints
2.
3.
The treatment is mainly supportive. Surgical excision of the lesions affecting the airway or oral cavity, pain relief by analgesics and timely treatment of infections need to be done.
Acknowledgments A to Z Genetic Services, Mumbai: For the mutation analysis of ANTXR2.
4.
5.
Landing BH, Nadorra R. Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis. Pediatr Pathol. 1986;6:55–79. Al-Mubarak L, Al-Makadma A, Al-Khenaizan S. Infantile systemic hyalinosis presenting as intractable infantile diarrhea. Eur J Pediatr. 2009;168:363–5. Al-Mayouf SM, Al Mehaidib A, Bahabri S, Shabib S, Sakati N, Teebi AS. Infantile systemic hyalinosis: a fatal disorder commonly diagnosed amongArabs. Clin Exp Rheumatol. 2005;23:717–20. Hanks S, Adams S, Douglas J, et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73:791–800. El-Kamah GY, Fong K, El-Ruby M, et al. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis. Br J Dermatol. 2010;163:213–5.
SCIENTIFIC LETTER
Infantile Systemic Hyalinosis with Mutation in ANTXR2 Dhanya Lakshmi Narayanan 1 & Shubha R. Phadke 1
Received: 4 July 2015 / Accepted: 10 December 2015 # Dr. K C Chaudhuri Foundation 2016
To the Editor: Infantile systemic hyalinosis (OMIM 236490) is a rare autosomal recessive disorder characterized by deposition of hyaline in skin, gingiva, adrenals, skeletal muscles and gastro intestinal tract [1, 2]. It presents in a new born or in early infancy with painful movements, joint contractures, gingival nodules, progressive skin thickening and hyperpigmented patches over bony prominances [3] and is caused by homozygous or compound heterozygous mutations in ANTXR2 on 4q21, which encodes capillary morphogenesis protein 2(CMG2) [4]. Mutation analysis is essential in confirming the diagnosis and offering prenatal diagnosis. We report a case of 2-mo-old boy with a homozygous mutation in ANTXR2. To our knowledge this is the first mutation proven case being reported from North India. A 2-mo-old boy who was the second child of third degree consanguineous parents had excessive cry during handling noticed since birth. Antenatal period of the mother was uneventful. He also had progressively increasing joint contractures of both elbows, ankles and knees with thick and shiny skin. He did not have chronic diarrhea and was gaining weight adequately. His elder sibling was a 3-y-old girl who was normal. On examination, he was very irritable and cried when touched. He had hyperpigmented macules over dorsum of hands over the knuckles, knees and on both malleoli. Skin
* Shubha R. Phadke [email protected]; [email protected] 1
Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute, Lucknow, Uttar Pradesh 226014, India
was indurated and thickened (Fig. 1). He had contracture of bilateral elbows, knees and ankles. He did not have gingival nodules or perianal papules or tags. His weight was 4 kg, length 52 cm and head circumference 34 cm (Normal for age). He did not have hepatosplenomegaly. Routine hematology and serum chemistry were normal. Radiographs did not show osteopenia or lytic lesions. Mutation analysis of ANTXR2 was done by Sanger sequencing and a homozygous c.1073_1074insC in exon 13 was identified. This mutation is a previously described disease causing mutation. Infantile systemic hyalinosis was first described by Landing and Nadorra in 1986 [1]. Systemic infantile hyalinosis should be suspected in a newborn or infant presenting with excessive cry during handling, skin thickening, hyperpigmented skin over bony prominences and joint contractures [1, 2]. Other features include gingival thickening, pearly white skin papules, perianal fleshy lesions and failure to thrive. Thickened skin can be seen in other conditions like Winchester syndrome, congenital fascial dystrophy, infantile restrictive dermopathy, Farber disease, I cell disease and mucolipidosis III A. The presence of characteristic purplish patches over the malleoli, metacarpophalangeal joints, elbow and spine is a distinctive clinical clue that helps to establish the diagnosis. Till date 25 different mutations in ANTXR2 have been described [5]. Two cases were reported from India previously, but molecular diagnosis was not done. Since it is inherited in an autosomal recessive manner, there is 25 % chance of recurrence in subsequent pregnancies. Hence, clinical suspicion and molecular diagnosis is very essential to provide prenatal diagnosis in subsequent pregnancies.
Indian J Pediatr Compliance with Ethical Standards Conflict of Interest None. Source of Funding None. Consent Informed consent from the relatives of the patient has been obtained.
References 1. Fig. 1 Photograph of the child showing (a) hyperpigmented macules on knuckles (b) hyperpigmented macules on medial malleoli (c) contractures of joints
2.
3.
The treatment is mainly supportive. Surgical excision of the lesions affecting the airway or oral cavity, pain relief by analgesics and timely treatment of infections need to be done.
Acknowledgments A to Z Genetic Services, Mumbai: For the mutation analysis of ANTXR2.
4.
5.
Landing BH, Nadorra R. Infantile systemic hyalinosis: report of four cases of a disease, fatal in infancy, apparently different from juvenile systemic hyalinosis. Pediatr Pathol. 1986;6:55–79. Al-Mubarak L, Al-Makadma A, Al-Khenaizan S. Infantile systemic hyalinosis presenting as intractable infantile diarrhea. Eur J Pediatr. 2009;168:363–5. Al-Mayouf SM, Al Mehaidib A, Bahabri S, Shabib S, Sakati N, Teebi AS. Infantile systemic hyalinosis: a fatal disorder commonly diagnosed amongArabs. Clin Exp Rheumatol. 2005;23:717–20. Hanks S, Adams S, Douglas J, et al. Mutations in the gene encoding capillary morphogenesis protein 2 cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Am J Hum Genet. 2003;73:791–800. El-Kamah GY, Fong K, El-Ruby M, et al. Spectrum of mutations in the ANTXR2 (CMG2) gene in infantile systemic hyalinosis and juvenile hyaline fibromatosis. Br J Dermatol. 2010;163:213–5.
