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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

AIAN-27-453
10.4103/aian.aian_102_24
Letters to the Editor
A Curious Case of Proximal Muscle Weakness with Intermittent Exacerbations
Gupta Diksha
Palayullakandi Achanya
Panda Prateek K.
Sharawat Indar K.
Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India
Address for correspondence: Dr. Indar K. Sharawat, Additional Professor and Chief, Pediatric Neurology Unit, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh - 249 203, Uttarakhand, India. E-mail: sherawatdrindar@gmail.com
Jul-Aug 2024
20 5 2024
27 4 453454
11 2 2024
03 4 2024
11 4 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
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pmcDear Editor,

A 10-year-old girl born to third-degree consanguineous parents presented with a previous history of four discrete episodes of abrupt-onset symmetric flaccid quadriparesis, affecting the lower limbs and the proximal muscles more and lasting for a few hours to days with no bulbar or respiratory involvement. This was not precipitated by fever, excessive exercise, rest after exercise, or a carbohydrate meal. On examination, she had stage I hypertension and generalized hyperpigmentation, particularly over the skin creases and the buccal mucosa, with features suggestive of hyperandrogenism (acne, hirsutism, and ambiguous genitalia). She had labioscrotal fusion with a single opening, penoscrotal hypospadias, with the phallus length being 6.5 cm along with clitoromegaly (Prader score: 3). Neurologic examination showed reduced power in bilateral lower and upper limb muscles with hyporeflexia, intact cranial nerves, and higher mental functions. Given these findings, we considered the possibility of hypokalemic periodic paralysis secondary to congenital adrenal hyperplasia (CAH).

She had hypokalemia (1.5 mEq/L) and normal arterial blood gas parameters, other electrolytes, and lactate, but her serum creatinine phosphokinase (CPK) was elevated (756 IU/L). The electrocardiogram showed ST depression and flat P waves. Ultrasonography of the pelvis showed a uterus-like structure and remnants of mullerian structures. X-ray of the left wrist showed advanced bone age. Her serum testosterone levels were elevated (332 ng/dL). Parenteral potassium correction and hydrocortisone supplementation led to only partial resolution of weakness, despite normalizing serum potassium. Even after 2 weeks, proximal limb girdle weakness persisted, with persistently elevated serum CPK (723 IU/L) and myopathic electromyography. Workup for inflammatory myositis and other endocrinal myopathies was noncontributory. Whole exome sequencing detected homozygous, likely pathogenic missense variation in exon 8 of the CYP11B1 gene on chromosome 8 (c.1354G>C, p.Gly452Arg) and another homozygous, likely pathogenic variation in exon 31 of the PLEC gene on chromosome 8 (c.6523G>A, p.Glu2175Lys), suggesting coexistence of CAH due to 11-beta-hydroxylase deficiency and limb-girdle muscular dystrophy (LGMD)-17 in the girl. Parents were counseled accordingly and the girl was discharged on hydrocortisone and antihypertensives. They were made aware of the option of genital reconstructive surgeries in the future.

Hypokalemic periodic paralysis is a rare neuromuscular disorder that presents with a sudden onset of generalized weakness, which can be debilitating, but can also be treated easily with the correction of potassium.[1] However, before making a diagnosis of hypokalemic periodic paralysis, we need to rule out other causes of recurrent hypokalemia involving renal, adrenal, or thyroid dysfunction, renal tubular acidosis; diuretic, and laxative abuse. There are rare case reports of the coexistence of CAH and hypokalemic periodic paralysis, but no case report of CAH presenting with periodic paralysis.[2] Moreover, the baseline clinical weakness was very subtle, which was missed by previous clinicians and precluded the early diagnosis of coexisting LGMD. Autosomal recessive LGMD-17 (LGMDR17) is a rare genetic disorder caused by a homozygous mutation in the PLEC gene, leading to early childhood onset of proximal muscle weakness and atrophy without skin involvement.[3] Rapid progression of the disorder has been observed in some cases during adolescence. Initially reported in the Turkish kindred in 2010, the affected members developed contractures and became bedridden by young adolescence, and some expired by 40 years of age. Plectin serves as a large cytoskeletal crosslinker and a stabilizing protein for intermediate filaments. Various rare diseases, collectively known as plectinopathies, result from mutations in the human plectin gene (PLEC). One prevalent condition is the autosomal recessive disorder epidermolysis bullosa simplex (EBS) with muscular dystrophy (EBS-MD), characterized by skin blistering and progressive muscle weakness. In addition to EBS-MD, PLEC mutations contribute to conditions such as EBS with nail dystrophy, EBS-MD accompanied by a myasthenic syndrome, EBS with pyloric atresia, LGMDR17, and EBS-Ogna.[4] However, CAH stemming from 11-beta-hydroxylase deficiency is attributed to homozygous or compound heterozygous mutations in the CYP11B1 gene. This condition disrupts corticosteroid biosynthesis, causing an excess of androgens, virilization, and hypertension.[5] The underlying genetic anomaly leads to reduced synthesis of cortisol and corticosterone in the adrenal gland’s zona fasciculata, resulting in the accumulation of precursors like 11-deoxycortisol and 11-deoxycorticosterone.[6] The latter, a potent mineralocorticoid with salt-retaining properties, contributes to the development of arterial hypertension. While hypertension can often be asymptomatic or can present with nonspecific symptoms in children, virilization went unnoticed in this prepubertal female. Probably, as the symptoms of LGMD started manifesting, the muscle weakness caused by hypokalemia became more profound to cause periodic paralysis-like symptoms. Moreover, the girl did not have any other clinical features of inflammatory myositis like juvenile dermatomyositis or endocrinal myopathy; hence, we suspected LGMD clinically in our case. Although serum CPK can remain elevated in a minority proportion of cases with hypokalemic paralysis, persistent manifold elevation should always raise suspicion of underlying myositis or muscular dystrophy.[7]

Probably, the child had subclinical or minimal weakness due to LGMD-17 and the weakness increased in severity because of hypokalemia caused by CAH and became clinically apparent. LGMD-17 has variable age of onset and probably, if CAH was not present in this patient, it would have manifested later. We performed a thorough literature search of previous published cases, but could not identify coexistence of pathogenic mutations in these two particular genes. However, these two loci may be linked or inherited together, as both these loci are present on chromosome 8, albeit on different axons. Since the girl was born to third-degree consanguineous parents, there was probably significant gene pool sharing between the parents. The index case was homozygous for the same mutation on both loci. As usually observed in linkage analysis, the closer two loci are on a chromosome, the less likely they are to undergo recombination. Usually, the shorter the distance between two loci, the stronger is the linkage.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgements

On behalf of all authors, the corresponding author states that there is no conflict of interest and funding sources related to this article.
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