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In this post, we consider the differential diagnosis of pigmented skin streaks in a child and discuss how to interpret a mosaic karyotype. I also recorded a video explanation of this post. Comment below or on YouTube if you would like to see more of this video format!
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Video explanation here:
Questions
Question 56
A 4-year-old boy with global developmental delay presents for an evaluation. He has a G-tube that he relies on for feeding, and his weight and length are within normal limits. Physical exam is notable for absent speech, moderate hypotonia, hyperpigmented streaks on the back and abdomen, and coarse facial features. A karyotype from a buccal swab reveals the following:
mos 47,XY,+i(12)(p10)[21]/46,XY[9]
What is the most likely diagnosis?
Question 57
The molecular basis of the disorder in Question 56 is associated with the presence of which of the following?
Explanation
This 4-year-old boy with hypotonia, global developmental delay, and hyperpigmented streaks on his trunk has mosaic tetrasomy 12p, which is diagnostic of Pallister-Killian syndrome (PKS) (Question 56). Clinically, PKS is characterized by hypotonia, global developmental delay, a coarse facial appearance, seizures, and hypo or hyper-pigmented streaks or whorls throughout the body. The PKS phenotype is highly variable between patients and depends in part on the degree of mosaicism.
💡Remember: “PalliSTR-Killian has Pigmented STReaKs”
The underlying basis of PKS is the presence of an isochromosome (Question 57). One way that an isochromosome can arise is when a centromere divides transversely rather than longitudinally (see image below), producing an abnormal chromosome with two identical arms. As with other disorders involving somatic mosaicism, PKS occurs sporadically and is not inherited from a parent. Therefore, the recurrence risk for the parents of a child with PKS is very low.
Explanation of karyotype nomenclature (Question 56)
Let’s break down the karyotype mentioned in Question 56:
mos 47,XY,+i(12)(p10)[21]/46,XY[9]
“mos” — The “mos” refers to “mosaic,” meaning that some cells contain one karyotype, and other cells contain a different karyotype.
“47,XY,+i(12)(p10)[21]” — The number "47" indicates the number of chromosomes in the first cell line. The "XY" signifies the presence of one X and one Y chromosome. The "+" indicates the presence of an extra chromosome. The "i" stands for "isochromosome," which is a chromosome made of 2 identical copies of a chromosomal arm. Specifically, this karyotype is referring to an isochromosome involving chromosome 12, hence the i(12). The "(p10)" describes the breakpoint location; in this case, p10 reflects that fact that the breakpoint is at the centromere of chromosome 12. Therefore, this isochromosome 12 has two identical p arms and no q arm. The "[21]" following the karyotype indicates that 21 cells were observed with the 47,XY,+i(12)(p10) karyotype during the analysis.
“/46,XY[9]” — The forward slash (“/”) separates the karyotype observed in the first cell line from that observed in the second cell line. In this case, we are looking at a normal male karyotype, 46,XY. The "[9]" indicates that this normal karyotype was observed in 9 cells during the analysis. The percent mosaicism is calculated as the % of cells with an abnormal karyotype. In this case, the percent mosaicism is 21/(21 + 9) = 0.7, or 70%. In general, the higher the percent mosaicism, the more affected a patient will be. The percent mosaicism can vary between tissues and also within the same tissue (e.g. 2 skin punch biopsies obtained from different sites might show a different percent mosaicism).
In summary, this karyotype describes a mosaic male with two different cell lines: one with an extra isochromosome of chromosome 12 (i.e. tetrasomy 12p) and the other with a typical male karyotype.
Incorrect answer choices (Question 56):
All of the incorrect answer choices in question 56 are associated with pigmentary abnormalities. We discuss the differentiating features below
Incontinentia pigmenti (IP) is an X-linked dominant condition that is male lethal and that leads to skin abnormalities due to ectodermal dysplasia. It manifests with a sequence of skin changes, beginning with blistering in infancy and followed by a wart-like rash, hyperpigmented streaks, and finally linear hypopigmentation. In contrast to PKS, where the pigmentary anomalies are typically present from birth, the pigmentary changes in IP evolve over time and are not present at birth. About 2/3 of patients with IP have a de novo 11.7-kb deletion involving IKBKG on chr Xq28 that would not be visible by karyotype.
💡Think “InKontinentia BiGmenti” to help remember IKBKG. Also, in incontinentia PigmenTi, the Pigment takes Time to appear.
Hypomelanosis of Ito (HI) is not a distinct clinical entity but rather a sign of somatic mosaicism that can have different underlying genetic etiologies. Patients with HI have streaky, whirled hypopigmentation (vs hyperpigmentation seen in the patient with IP in Question 56). While mosaicism is a key feature of HI, mosaicism of isochromosome 12p with hyperpigmented streaks and developmental delay is more typical of Pallister-Killian.
Focal dermal hypoplasia: This is an X-linked dominant condition associated with patchy skin aplasia, hyper- & hypopigmentation following the lines of Blaschko, and hypoplastic nails. Additional features include limb anomalies (e.g. syndactyly, oligodactyly, ectrodactyly), facial asymmetry, and a variety of ocular abnormalities. The condition results from pathogenic variants in the PORCN gene (encodes a Porcupine O-acyltransferase) and is not associated the presence of an isochromosome.
Incorrect answer choices (Question 57):
Polyploidy: The typical human genome is diploid, meaning there are 2 copies of each chromosome (aside from the sex chromosomes). Polyploidy is defined as 3 or more copies of the genome. While certain cell types, such as placenta and hepatocytes, have been shown to be polyploid, polyploidy that affects the entire fetus (e.g. triploidy, or 69,XXY) is not viable and results in miscarriage.
Pericentric inversion: This is a chromosomal rearrangement where a segment of the chromosome that includes the centromere undergoes inversion. One example of a pericentric inversion is inv(8) that affects chromosome 8. Carriers of inv(8) are asymptomatic but are at increased risk for having a child with recombinant 8 syndrome (aka rec(8)), which presents with multiple congenital anomalies.
Ring chromosome: This occurs when a chromosome undergoes breakage in both arms, followed by the fusion of the broken ends to form a ring-like structure. Ring chromosomes can cause genetic syndromes (e.g. ring chromosome 20 syndrome) but are not associated with PKS.
Robertsonian translocation: This translocation involves two acrocentric chromosomes fusing near the centromere region with the loss of the short arms. Carriers of Robertsonian translocations are at risk of recurrent miscarriage and/or of having a child with an autosomal trisomy (e.g. trisomy 13, trisomy 21) if one of these chromosomes is involved.
Learning objective
Pallister-Killian syndrome (PKS) is a mosaic disorder caused by the presence of an extra isochromosome 12p (tetrasomy 12p). Patients presents with developmental delay, hypotonia, and pigmented skin streaks that are present from birth. The diagnosis of PKS is made with a karyotype. In general, the presence of whorled or streaky pigmentary changes on the skin should prompt consideration of somatic mosaicism.
2023 ABMGG General Exam Blueprint | IV. Cytogenetics → b. Chromosome abnormalities → iii) Mosaicism/chimerism
2023 ABGC Exam Content Outline | Domain 1. Clinical Information, Human Development, and Genetic Conditions → C. Genetic Conditions → 6. Diagnostic processes including clinical criteria and testing strategy & 8. Etiology
References
Pallister-Killian syndrome: clinical, cytogenetic and molecular findings in 15 cases
Pallister-Killian syndrome (OMIM)