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Early puberty

Maternal and paternal heritages play equal role in genetic disorder causing premature onset of puberty

Léo Ramos Chaves/Revista Pesquisa FAPESP

Parents often worry about the timing of their children’s entry into puberty, a period marked by significant changes in both physical and psychological development. Of particular concern is the occurrence of precocious puberty, a relatively rare condition affecting less than 0.5% of the population. Precocious puberty is typically diagnosed based on the emergence of secondary sexual characteristics like breast development, axillary and pubic hair growth, and accelerated bone development. When puberty commences before the age of 8 in girls or before the age of 9 in boys, doctors will commonly recommend hormonal puberty blockers, a service available from the Brazilian National Healthcare System (SUS). Researchers in the field are exploring the hereditary mechanisms behind precocious puberty, among them a team led by Ana Claudia Latronico, an endocrinologist at a teaching hospital affiliated with the University of São Paulo School of Medicine (FM-USP).

There are two main types of early puberty: central and peripheral. Central precocious puberty (CPP) differs from peripheral precocious puberty (PPP) in that it originates within the central nervous system. It is the most common cause of early puberty. CPP prematurely activates the axis connecting the hypothalamus (which coordinates most endocrine functions), the pituitary gland, and the gonads, resulting in the production of sex hormones. In contrast, PPP leads to an increase in these same hormones without the regulatory influence of the hypothalamus.

The scientific community has primarily searched for the causes of CPP in factors such as tumors, lesions in the central nervous system, and complex syndromes. Genetic causes were largely overlooked until 2013 when Latronico’s team discovered defects in a gene frequently associated with the condition, MKRN3, located on chromosome 15. Now, the group has found that central precocious puberty is inherited as often from the mother as from the father, as reported in an article published in January in the Journal of Clinical Endocrinology & Metabolism.

In the families evaluated by Latronico, cases of precocious puberty skipped generations: the condition would often be absent in the children of affected women but reemerge in the next generation. “The lack of a clear transmission pattern in families has baffled researchers investigating central precocious puberty,” she says about the discovery of the genetic influence by MKRN3. Her group eventually found that this is a case of imprinting, where the expression of a specific gene is silenced under particular circumstances. This means that, even though the gene is present in the DNA, it may not give rise to the trait it codes for.

For MKRN3-induced CPP, what matters is who transmits the gene. If it is passed on by the father, then his children will inherit the condition. If the mother transmits it, the gene is silenced by chemical mechanisms that alter DNA function, and the child enters puberty at a normal age, after 8 or 9 years old.

The onset of puberty outside the typical timeframe, whether earlier or later, has both mental and physical implications for the child. Both central and peripheral precocious puberty lead to medical concerns about growth. Early activation of sex hormones triggers an initial and accelerated growth spurt. As a result, the growth plates in long bones close prematurely, stunting the child’s growth. Without treatment, precocious puberty leads to abnormally short stature in adulthood. CPP is approximately 20 times more common in girls than in boys. In addition to the impact on height, other potential medical consequences include obesity, high blood pressure, and cardiovascular disease, explains Latronico.

For Marlene Inácio, a psychologist at a teaching hospital who primarily works with children aged 5 to 12 experiencing precocious puberty, the behavioral changes that come with a diagnosis result from both hormonal shifts and psychosocial factors. She notes that children with CPP grapple with changes in their appearance and feelings of isolation and shame compared to others their age. “Children often present with symptoms of stress, anxiety, and even depression,” says Inácio.

The lack of a clear transmission pattern has baffled researchers investigating central precocious puberty

Latronico’s group became a global authority in the field when, in 2017, they identified a second gene responsible for precocious puberty, DLK1, located on chromosome 14. In a study in collaboration with universities in the US and Spain, involving children with precocious puberty seen at a USP outpatient clinic, DLK1 was identified as another cause of the familial form of CPP. The DLK1 mutation, which is much rarer than its MKRN3 counterpart, is associated with metabolic obesity in adulthood and is passed on by the father only. “This leads us to believe that epigenetics plays a central role in development and the onset of puberty,” says Latronico, referring to the effect of environmental conditions on the activation or deactivation of genes, which can be passed from one generation to another.

Approximately 40% of children with familial CPP have a mutation in MKRN3, which is highly significant, while only about 4% of cases are caused by DLK1 — the cause of the other 56% of cases is yet to be determined. These proportions are similar in all countries and ethnic groups covered in the study. The group’s findings suggested that paternal genes subject to imprinting play an important role in controlling puberty. What the USP group still needed to determine was the extent to which maternal genes are involved in this condition.

When endocrinologist Flávia Tinano approached Latronico’s laboratory to pursue her doctoral studies in 2018, the lead researcher was intrigued by observations that, in addition to families affected by the paternally transmitted MKRN3, there were also children who inherited the condition directly from their mothers. Tinano was tasked with reviewing the data on previously collected samples from 276 children with familial central precocious puberty. The researchers have not reached a definitive conclusion from the genes being considered as candidates for the observed pattern, but they have confirmed that inheriting central precocious puberty from the mother is not unusual.

“I used to see cases at the clinic where the grandmother, mother, and daughter displayed symptoms, so I knew they had no connection to MKRN3,” Latronico explains. “I won’t deny that I had high expectations of finding the genetic cause for maternal inheritance of CPP, as we did with MKRN3 and DLK1.” But Tinano’s research did conclusively establish the equal role of paternal and maternal inheritance and opened up new avenues for investigation.

The answer may lie in the regulatory regions of the genome rather than specific genes themselves. “Or perhaps it’s in mitochondrial genes, which are not in the nuclear DNA,” Latronico speculates. “In any case, we plan to build further on this research in the near future.”

Understanding the genetic causes can aid physicians in managing the condition and initiating treatment as early as possible. “We explain the mode of transmission to families planning to have children, helping to avoid the common occurrence of children coming to the clinic when height impairment is inevitable due to the advancement of bone age,” says Tinano. Treatment is based on an analogue of the sex hormone produced by the hypothalamus, GnRH, which is not produced during normal puberty.

Marlene Inácio has observed posttreatment improvement in psychological well-being in the children she sees. She describes them as “less anxious and less stressed,” noting that providing care up to the time the medication is discontinued, at age 12, results in better quality of life and increased sociability.

Scientific article
MEDEIROS, P. C. de S. et al. Puberdade precoce e as consequências emocionais no desenvolvimento infantil. Revista Eletrônica Acervo Saúde. vol. 13, no. 4. apr. 29, 2021.