Endocrinol Metab.  2018 Jun;33(2):252-259. 10.3803/EnM.2018.33.2.252.

Novel Mutation in PTHLH Related to Brachydactyly Type E2 Initially Confused with Unclassical Pseudopseudohypoparathyroidism

• Bae J
• Choi HS
• Park SY
• Lee DE
• Lee S

• KMID: 2420494
• DOI: http://doi.org/10.3803/EnM.2018.33.2.252

Abstract

BACKGROUND
Autosomal-dominant brachydactyly type E is a congenital abnormality characterized by small hands and feet, which is a consequence of shortened metacarpals and metatarsals. We recently encountered a young gentleman exhibiting shortening of 4th and 5th fingers and toes. Initially, we suspected him having pseudopseudohypoparathyroidism (PPHP) because of normal biochemical parameters, including electrolyte, Ca, P, and parathyroid hormone (PTH) levels; however, his mother and maternal grandmother had the same conditions in their hands and feet. Furthermore, his mother showed normal biochemical parameters. To the best of our knowledge, PPHP is inherited via a mutated paternal allele, owing to the paternal imprinting of GNAS (guanine nucleotide binding protein, alpha stimulating) in the renal proximal tubule. Therefore, we decided to further analyze the genetic background in this family.
METHODS
Whole exome sequencing was performed using genomic DNA from the affected mother, son, and the unaffected father as a negative control.
RESULTS
We selected the intersection between 45,490 variants from the mother and 45,646 variants from the son and excluded 27,512 overlapping variants identified from the father. By excluding homogenous and compound heterozygous variants and removing all previously reported variants, 147 variants were identified to be shared by the mother and son. Variants that had least proximities among species were excluded and finally 23 variants remained.
CONCLUSION
Among them, we identified a defect in parathyroid hormone like hormone (PTHLH), encoding the PTH-related protein, to be disease-causative. Herein, we report a family affected with brachydactyly type E2 caused by a novel PTHLH mutation, which was confused with PPHP with unclassical genetic penetrance.

Keyword

Brachydactyly; Pseudopseudohypoparathyroidism; Parathyroid hormone like hormone; Parathyroid hormone-related protein

MeSH Terms

Alleles
Brachydactyly*
Carrier Proteins
Congenital Abnormalities
DNA
Exome
Fathers
Fingers
Foot
Genetic Background
Grandparents
Hand
Humans
Metacarpal Bones
Metatarsal Bones
Mothers
Parathyroid Hormone
Parathyroid Hormone-Related Protein
Penetrance
Pseudopseudohypoparathyroidism*
Toes
Carrier Proteins
DNA
Parathyroid Hormone
Parathyroid Hormone-Related Protein

Figure

• 

  Fig. 1 Pedigree of this family. Brachydatylies are found in every generations in both genders indicating autosomal dominant trait of inheritance. Open, unaffected; closed, affected. aProband.

• 

  Fig. 2 Clinical phenotypes of the proband and his mother: (A) right hand of the proband; (B) left hand of the mother; (C) right foot of the proband; (D) left foot of the mother, note the shortening of the 4th and 5th metacarpals and 4th and 5th metatarsals; (E) radiological feature of the mother's left feet showing shortening of 4th and 5th metatarsals. In addition, premature fusion of the epiphyses is noted in the shortened bones.

• 

  Fig. 3 Filters used in analysis of the exome data and numbers of candidate variants. The autosomal dominant variants identified by whole exome sequencing were represented by the Venn diagram. After filtering, a total of 8,908 variants were identified as being shared by the two affected subjects.

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  Fig. 4 Schematic structure of PTHLH (parathyroid hormone like hormone) gene. Mutations reported in the literature that were associated with brachydactyly type E are indicated in black in addition to the c.169C>T mutation identified in this study in red.

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