Atrichia with papular lesions (APL)

APL is inherited in an autosomal recessive manner. Parents of an affected individual are obligate heterozygous carriers and are typically asymptomatic; with each pregnancy of two carrier parents, the recurrence risk for an affected child is 25%. Consanguinity increases the likelihood of biallelic HR variants and is reported in many published families. Carrier testing of at-risk relatives and prenatal molecular testing are technically possible once the familial pathogenic variants in HR have been identified.

The clinical diagnosis rests on the Zlotogorski criteria for atrichia with papular lesions (1998), later revised by Yip et al. (2008), which require fulfilment of three of five major and three of five auxiliary criteria. Meeting these criteria establishes the clinical diagnosis of APL. Scalp biopsy demonstrates reduced or absent hair follicles together with keratin-filled horn cysts; histology is supportive, while identification of biallelic pathogenic variants in HR provides definitive molecular confirmation.

Main differential diagnoses include:

• Alopecia universalis congenita (AUC): total congenital alopecia without follicular-based keratotic papules or milia-like cysts; scalp biopsy shows atrophic or absent follicles but lacks horn cysts; HR
• Hereditary vitamin D-dependent rickets type IIA (VDDR-IIA, HVDRR): total alopecia with concomitant early-onset rickets, hypocalcaemia, and skeletal manifestations; VDR
• Alopecia areata totalis/universalis (autoimmune): non-scarring hair loss with later onset (~6 years), patchy progression, nail dystrophy, and atopy association; non-Mendelian (polygenic/HLA-associated)

• Establishing the diagnosis through identification of the underlying pathogenic variant(s), thereby confirming the clinical suspicion at the molecular level.
• Enabling clinical management informed by the molecular diagnosis as a prerequisite for targeted medical care, decided by the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant(s) is a prerequisite for predictive testing of at-risk relatives and for reproductive counselling within the family.

• Rand MR, Yale K, Kato BS, Kim DJ, Birmingham S, Mesinkovska NA. Commonly associated disorders with complete scalp alopecia in early childhood: a review. Int J Trichology. 2023;15(2):43-9. doi:10.4103/ijt.ijt_70_22. PMID:; PMCID: PMC10495068.
• Boisen J, Lewis J, Hendrick SJ. Atrichia with papular lesions confirmed via genetic testing: a case report. Cureus. 2022;14(12). doi:10.7759/cureus.32562. PMID:; PMCID: PMC9840447.
• Tunuguntla MN, Mathew B, Quadri A, Movva S, Raghavan P, Rajpal S, et al. Inherited hairlessness: a case study of familial congenital atrichia. Cureus. 2023;15(4). doi:10.7759/cureus.37608. PMID:; PMCID: PMC10184725.
• Ullah K, Ahmed S, Cesarato N, Xiong X, Taj M, Manan N, et al. Novel pathogenic variants in HR underlie atrichia with papular lesions in a cohort of 10 families. J Dermatol. 2025;52(3):515-9. doi:10.1111/1346-8138.17349. PMID:.